Arylamide Compounds And Compositions And Uses Thereof

ABSTRACT

The present invention discloses ophthalmic and otic compositions of facially amphiphilic antimicrobial polymers and oligomers and their uses, including their use in methods for treating and preventing ophthalmic infections and otic infections in humans and animals.

FIELD OF THE INVENTION

The present invention relates to antimicrobial compositions of faciallyamphiphilic antimicrobial polymers and oligomers useful for thetreatment or prevention of ophthalmic and otic infections. The presentinvention also relates to methods of using the compositions for treatingand/or preventing ophthalmic and otic infections.

BACKGROUND OF THE INVENTION

Bacterial drug resistance is a significant current health problemthroughout the world. Multiple drug resistance is being commonly seen ina number of human pathogens (see, e.g., Hiramatsu et al., J. Antimicrob.Chemother., 1998, 40, 311-313 and Montecalvo et al., Antimicro. AgentsChemother., 1994, 38, 1363-1367, and the incidence of drug-resistanthospital infections is growing at a rapid rate. For example, in someU.S. hospitals, nosocomial pathogens, such as E. faecium andAcinetobacter species, have acquired multiple resistance determinantsand are virtually untreatable with current antimicrobial agents.Bacterial resistance has now reached epidemic proportions and has beenattributed to a variety of abuses of antibiotic treatments, includingoveruse (Monroe et al., Curr. Opin. Microbiol., 2000, 3, 496-501),inappropriate dosing at sub-therapeutic levels (Guillemot et al., JAMA,1998, 279, 365-370), and misuse as antimicrobial growth promoters inanimal food (Lathers, J. Clin. Pharmacol., 2002, 42, 587-600). Moreover,the threat of bio-terrorism has provided a further impetus to developnovel classes of antibiotics, particularly ones against which it will bedifficult to develop resistant bacterial strains.

The pharmaceutical scientific community is responding to this challengeby focusing on the development of new antibiotic drugs. Much of thiswork, however, is directed to synthesizing analogs of known drugs, suchas cephalosporins and quinolones, that, while potentially useful for ashort time, will inevitably also encounter bacterial drug resistance andbecome ineffective. Thus, therapeutically effective antimicrobial drugsthat act by novel mechanisms would provide an economic as well as ahuman health benefit.

A series of nonpeptidic mimics of the natural antimicrobial peptideshave been developed that are polymers, oligomers and small moleculescomprised of non-natural building blocks. See, Tew et al., Proc. Natl.Acad. Sci. U.S.A., 2002, 99, 5110-5116; Arnt et al., J. Polym. Sci.,Part A, 2004, 42, 3860-3864; and Liu et al., Angew Chem. Int. Ed. Engl.,2004, 43, 1158-1162. Many of these compounds are significantly smallerand easier to prepare than the natural antimicrobial peptides andpeptidic mimetics, with the shortest of these oligomers having molecularweights typical of small molecule drugs. They have the same mechanism ofaction as magainin, are highly potent and have a broad spectrum ofactivity, killing gram-positive, gram-negative and antibiotic-resistantpathogens. Relative to the antimicrobial peptides, the non-peptidicmimetics are significantly less toxic towards human erythrocytes, muchless expensive to prepare, and more stable.

See, for example, U.S. Published Patent Appl. Nos. US 2006-0041023 A1,US 2004-0202639 A1, US 2005-0287108 A1, and US 2006-0024264 A1, and U.S.Pat. No. 7,173,102.

There is a great need for improved compositions and methods of treatmentbased on the use of antimicrobials that are more effective than existingagents against key ophthalmic and otic pathogens, and less prone to thedevelopment of resistance by those pathogens. In particular, there is agreat need for effective compositions and methods for the treatment ofotic infections, especially bacterial infections. The use of oralantibacterials to treat otic infections in children has limited efficacyand creates a serious risk of pathogen resistance to the orallyadministered antibacterial agent.

Thus, a need remains for improved ophthalmic and otic antimicrobialcompositions, in particular, for broad-spectrum antimicrobial agentsuseful for the treatment of ophthalmic and otic infections that are notprone to the development of resistance by ophthalmic and/or oticpathogens and that are effective in the treatment of ophthalmic and oticpathogens that have already developed resistance to existingantimicrobial agents.

SUMMARY OF THE INVENTION

The present invention provides compositions of antimicrobial,amphiphilic polymers and oligomers or Formulae I, II, IV, V, and VI,

R¹—[-X-A₁-Y—X-A₂-Y-]_(m)—R²  (I)

R¹—[-X-A₁-X—Y-A₂-Y-]_(m)—R²  (II)

R¹—[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  (IV)

R¹[-A₁-W-A₂-W-]_(m)—R²  (V)

A-(B)_(n1)-(D)_(m1)-H  (VI)

or acceptable salts or solvates thereof, wherein R¹, R², A₁, A₂, A, B,D, X, Y, Z, W, m, m1, and n1 are as defined below, includingantimicrobial compositions that can be administered for the treatment orprevention of ophthalmic and otic infections in humans or animals.

The amphiphilic polymers and oligomers useful in the present inventioninclude, but are not limited to, polyamide and polyester compounds ofFormulae I and II wherein X is O, NR³, or S, Y is C═O, C═S, or SO₂, andA₁ and A₂ are aromatic, heteroaromatic, or aliphatic moietiesappropriately substituted with one or more polar and/or nonpolar groups;polyurea, polycarbamate, and polycarbonate compounds of Formula IVwherein X and Y are O, NR³, or S, Z is C═O, C═S, or SO₂, and A₁ and A₂are aromatic, heteroaromatic, or aliphatic moieties appropriatelysubstituted with one or more polar and/or nonpolar groups. Also usefulin the present invention are amphiphilic polyaryl and polyarylalkynylpolymers and oligomers of Formula V wherein W is —CH₂—, —CH₂—CH₂—,—CH═CH—, or —C≡C—, and A₁ and A₂ are aromatic or heteroaromatic moietiesappropriately substituted with one or more polar and/or nonpolar groups;and random methacrylate copolymers of Formula VI wherein R¹ and R² areend groups appropriate for the specific polymer or oligomer and are asdefined below.

Thus, the present invention is directed to an ophthalmic composition,comprising an effective amount of an antimicrobial polymer or oligomerof Formula I as disclosed herein, or an acceptable salt or solvatethereof, and an ophthalmically acceptable excipient.

The present invention is also directed to an ophthalmic composition,comprising an effective amount of an antimicrobial polymer or oligomerof Formula II as disclosed herein, or an acceptable salt or solvatethereof, and an ophthalmically acceptable excipient. In someembodiments, the antimicrobial oligomer of Formula II has Formula IIa asdisclosed herein.

The present invention is further directed to an ophthalmic composition,comprising an effective amount of an antimicrobial polymer or oligomerof Formula IV as disclosed herein, or an acceptable salt or solvatethereof, and an ophthalmically acceptable excipient. In someembodiments, the antimicrobial oligomer of Formula IV has Formula IVa,Formula IVb, or Formula IVc as disclosed herein.

The present invention is also directed to an ophthalmic composition,comprising an effective amount of an antimicrobial polymer or oligomerof Formula V as disclosed herein, or an acceptable salt or solvatethereof, and an ophthalmically acceptable excipient. In someembodiments, the antimicrobial oligomer of Formula V has Formula Va asdisclosed herein.

The present invention is further directed to an ophthalmic composition,comprising an effective amount of an antimicrobial random polymer oroligomer of Formula VI as disclosed herein, or an acceptable salt orsolvate thereof, and an ophthalmically acceptable excipient.

The present invention is also directed to an antimicrobial ophthalmiccomposition, the composition comprising a) an antimicrobial oligomer ofFormula I, Formula II, Formula IIa, Formula IV, Formula IVa, FormulaIVb, Formula IVc, Formula V, Formula Va, or Formula VI as disclosedherein, or a pharmaceutically acceptable salt or solvate thereof, in anamount effective for treatment and/or prophylaxis of a microbialinfection of an eye of an animal; and b) an ophthalmically acceptableexcipient, wherein the composition is suitable for administration to oneor more tissues of the eye.

The present invention is also directed to an ophthalmic composition foruse in treatment or prevention of a microbial infection in an eye of ananimal, wherein the improvement comprises employing an antimicrobialoligomer of Formula I, Formula II, Formula IIa, Formula IV, Formula IVa,Formula IVb, Formula IVc, Formula V, Formula Va, or Formula VI asdisclosed herein, or an acceptable salt or solvate thereof, in thecomposition in an amount effective to treat or prevent the infectionwhen the composition is administered to one or more tissues of the eye.

The present invention is also directed to any of the ophthalmiccompositions disclosed herein, wherein the composition is suitable fortopical administration to one or more tissues of an eye of an animal.

The present invention is also directed to any of the ophthalmiccompositions disclosed herein, wherein the composition is in a formselected from the group consisting of a solution, a suspension, anemulsion, a gel, an ointment, and a solid article suitable for ocularimplant.

The present invention is also directed to any of the ophthalmiccompositions disclosed herein, wherein the oligomer is present in thecomposition at a concentration of from about 0.01% to about 20% byweight.

The present invention is also directed to any of the ophthalmiccompositions disclosed herein, wherein the ophthalmically acceptableexcipient is selected from a preservative, a stabilizer, an antioxidant,an anti-inflammatory agent, a viscosity-enhancing agent, and an agent toprolong residence time of the oligomer in ocular tissue, or anycombination thereof.

The present invention is also directed to use of the compounds andcompositions of the invention in the preparation of a medicament fortreating or preventing ophthalmic and/or otic infections in a human oranimal.

In some embodiments of the ophthalmic compositions of the presentinvention, the preservative is selected from a phenylmercuric salt,thimerosal, stabilized chlorine dioxide, a quaternary ammonium compound,imidazolidinyl urea, a paraben, phenoxyethanol, chlorophenoxyethanol,phenoxypropanol, chlorobutanol, chlorocresol, phenylethyl alcohol, andsorbic acid and its salts, or any combination thereof.

In some embodiments, the antioxidant is selected from ascorbic acid,sodium metabisulfite, sodium bisulfite, and acetylcysteine.

In some embodiments, the stabilizer is a chelating agent, such as, forexample, disodium EDTA.

In some embodiments, the viscosity-enhancing agent is selected frommethylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, andglycerol.

In some embodiments, the ophthalmic composition further comprises anadditional ophthalmically acceptable excipient. The additionalophthalmically acceptable excipient is selected from a buffering agent,a solubilizing agent, a surfactant, a lubricating agent, and anophthalmically acceptable salt, or any combination thereof.

In some embodiments, the ophthalmic composition further comprises anadditional medicament. The additional medicament is selected from ananti-inflammatory agent, an antimicrobial agent, an anesthetic agent,and an anti-allergic agent.

The present invention is further directed to a method of treating orpreventing a microbial infection in an eye of an animal, comprisingadministering to an eye of an animal in need of the treating orpreventing an effective amount of an ophthalmic composition of thepresent invention.

The present invention is also directed to a method for treating orpreventing a microbial infection in an eye of an animal by administeringto one or more tissues of the eye an antimicrobial ophthalmiccomposition, wherein the composition comprises an antimicrobial oligomerof Formula I, Formula II, Formula IIa, Formula IV, Formula IVa, FormulaIVb, Formula IVc, Formula V, Formula Va, or Formula VI, as disclosedherein, in an amount effective to treat or prevent the infection.

In some embodiments of the methods of the present invention, theantimicrobial ophthalmic composition is administered topically to one ormore tissues of the eye of the animal.

In some embodiments of the methods present invention, the ophthalmiccomposition is in a form selected from a solution, a suspension, anemulsion, a gel, an ointment, and a solid article suitable for ocularimplant. In other embodiments, the ophthalmic composition isadministered 2 to 4 times daily. In yet other embodiments, the oligomerin the ophthalmic composition is present in the composition at aconcentration of about 0.01% to about 20% by weight.

In some embodiments of the methods of the present invention, themicrobial ophthalmic infection is a bacterial infection. For example, insome embodiments, the bacterial infection is caused by Staphylococcus,Streptococcus, Enterococcus, Bacillus, Corynebacterium, Moraxella,Haemophilus, Serratia, Pseudomonas, or Neisseria spp. In otherembodiments, the microbial infection is a fungal infection. For example,in some embodiments, the fungal infection is caused by Aspergillus orFusarium spp. In yet other embodiments, the microbial infection is aviral infection. For example, in some embodiments, the viral infectionis caused by a herpes virus. In some embodiments of the methods of thepresent invention, the ophthalmic infection is selected from bacterialkeratitis, bacterial conjunctivitis, and corneal ulcers.

The present invention is also directed to an otic composition,comprising an effective amount of an antimicrobial oligomer or polymerof Formula I, Formula II, Formula IV, Formula V, or Formula VI, or anacceptable salt or solvate thereof, and an otically acceptableexcipient.

The present invention is also directed to an antimicrobial oticcomposition, the composition comprising a) an antimicrobial oligomer ofFormula I, Formula II, Formula IIa, Formula IV, Formula IVa, FormulaIVb, Formula IVc, Formula V, Formula Va, or Formula VI, or apharmaceutically acceptable salt or solvate thereof, in an amounteffective for treatment and/or prophylaxis of a microbial infection ofan ear of an animal; and b) an otically acceptable excipient, whereinthe composition is suitable for administration to one or more tissues ofthe ear.

The present invention is also directed to an otic composition for use intreatment or prevention of a microbial infection in an ear of an animal,wherein the composition comprises an antimicrobial oligomer of FormulaI, Formula II, Formula IIa, Formula IV, Formula IVa, Formula IVb,Formula IVc, Formula V, Formula Va, or Formula VI as disclosed herein,or an acceptable salt or solvate thereof, in an amount effective totreat or prevent the infection when the composition is administered toone or more tissues of the ear.

The present invention is also directed to any of the otic compositionsdisclosed herein, wherein the composition is suitable for topicaladministration to one or more tissues of an ear of an animal.

The present invention is also directed to any of the otic compositionsdisclosed herein, wherein the composition is in a form selected from asolution, a suspension, an emulsion, a gel, an ointment, and a solidarticle suitable for otic implant.

The present invention is also directed to any of the otic compositionsdisclosed herein, wherein the polymer or oligomer is present in the oticcomposition at a concentration of about 0.01% to about 20% by weight.

The present invention is also directed to any of the otic compositionsdisclosed herein, wherein the otically acceptable excipient is selectedfrom a preservative, a stabilizer, an antioxidant, and aviscosity-enhancing agent, or any combination thereof.

In some embodiments of the otic compositions, the preservative isselected from a phenylmercuric salt, thimerosal, stabilized chlorinedioxide, a quaternary ammonium compound, imidazolidinyl urea, paraben,phenoxyethanol, chlorophenoxyethanol, phenoxypropanol, chlorobutanol,chlorocresol, phenylethyl alcohol, and sorbic acid and its salts, or anycombination thereof.

In some embodiments, the antioxidant is selected from ascorbic acid,sodium metabisulfite, sodium bisulfite, and acetylcysteine.

In some embodiments, the stabilizer is a chelating agent, such as, forexample, disodium EDTA.

In some embodiments, the viscosity-enhancing agent is selected frommethylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, andglycerol.

In some embodiments, the otic composition further comprises anadditional otically acceptable excipient. The additional oticallyacceptable excipient is selected from a buffering agent, a solubilizingagent, a surfactant, a lubricating agent, and an ophthalmicallyacceptable salt, or any combination thereof.

In some embodiments, the otic composition further comprises anadditional medicament. The additional medicament is selected from ananti-inflammatory agent, an antimicrobial agent, an anesthetic agent,and an anti-allergic agent.

The present invention is further directed to a method of treating orpreventing a microbial infection in an ear of an animal, the methodcomprising administering to an ear of an animal in need of the treatingor preventing an effective amount of an otic composition of the presentinvention.

The present invention is also directed to a method for treating orpreventing a microbial infection in an ear of an animal by administeringto one or more tissues of the ear an antimicrobial otic composition,wherein the composition comprises an antimicrobial oligomer of FormulaI, Formula II, Formula IIa, Formula IV, Formula IVa, Formula IVb,Formula IVc, Formula V, Formula Va, or Formula VI, as disclosed herein,in an amount effective to treat or prevent the infection.

In some embodiments of the methods of the present invention, theantimicrobial otic composition is administered topically to one or moretissues of the ear of the animal.

In some embodiments of the methods of the present invention, the oticcomposition is in a form selected from a solution, a suspension, anemulsion, a gel, an ointment, and a solid article suitable for oticimplant. In other embodiments, the otic composition is administered 2 to4 times daily. In yet other embodiments, the polymer or oligomer ispresent in the otic composition at a concentration of about 0.01% toabout 20% by weight.

In some embodiments of the methods of the present invention, themicrobial otic infection is a bacterial infection. In other embodiments,the infection is a fungal infection. In yet other embodiments, theinfection is a viral infection.

In some embodiments of the methods of the present invention, the oticinfection is selected from otitis externa and otitis media.

In particular, the present embodiments include, for example:

1) An ophthalmic composition, comprising an effective amount of anantimicrobial oligomer of Formula I:

R¹—[-X-A₁-Y—X-A₂-Y—]_(m)—R²  (I)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —N(R⁸)N(R⁸)—, O, or S;

Y is C═O, C═S, O═S═O, or —C(═O)C(═O)—;

R⁸ is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

A₁ is optionally substituted arylene or optionally substitutedheteroarylene and A₂ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein qis 1 to 7, wherein A₁ and A₂ are, independently, optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s); or

A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and A₁ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein qis 1 to 7, wherein A₁ and A₂ are, independently, optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar (PL) group, or a non-polar (NPL) group,        and R² is —X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a polar (PL)        group, or a non-polar (NPL) group; or    -   (ii) R¹ and R² are, independently, hydrogen, a polar (PL) group,        or a non-polar (NPL) group; or    -   (iii) R¹ and R² together are a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

-   -   the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with        one or more amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 20; and an ophthalmically acceptable excipient.

2) The composition of 1), wherein:

X is NR⁸;

Y is C═O;

R⁸ is hydrogen;

A₁ is optionally substituted o-, m-, or p-phenylene and A₂ is—(CH₂)_(q)—, wherein q is 1, and wherein one of A₁ and A₂ is substitutedwith one or two polar (PL) group(s), and the other of A₁ and A₂ issubstituted with one or two non-polar (NPL) group(s); or

A₂ is optionally substituted o-, m-, or p-phenylene and A₁ is—(CH₂)_(q)—, wherein q is 1, and wherein one of A₁ and A₂ is substitutedwith one or two polar (PL) group(s), and the other of A₁ and A₂ issubstituted with one or two non-polar (NPL) group(s);

R¹ and R² are, independently, hydrogen, a polar (PL) group, or anon-polar (NPL) group;

NPL is —(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R^(4′) is selected from C₁-C₁₀ alkyl, C₃-C₁₈ branched alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, and C₆-C₁₀ aryl, any of which is optionallysubstituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from NH, —C(═O)—, O, and S;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino groups;

pNPL is 0 to 8;

q1NPL and q2NPL are 0;

PL is —(NR^(5′))_(q1PL)—U^(PL)(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NH, and —C(═O);

V is selected from amino, C₁-C₆ alkylamino, —NH(CH₂)_(p)NH₂ wherein p is1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, and guanidino;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino groups;

pPL is 0 to 8;

q1PL and q2PL are 0; and

m is 4 or 5.

3) An ophthalmic composition, comprising an effective amount of anantimicrobial oligomer of Formula II:

R¹—[-X-A₁-X—Y-A₂-Y-]_(m)—R²  (II)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, O, S, —N(R⁸)N(R⁸)—, —N(R⁸)—(N═N)—, —(N═N)—N(R⁸)—,—C(R⁷R^(7′))NR⁸—, —C(R⁷R^(7′))O—, or —C(R⁷R^(7′))S—;

Y is C═O, C═S, O═S═O, —C(═O)C(═O)—, C(R⁶R⁶)C═O, or C(R⁶R⁶)C═S;

R⁸ is hydrogen or alkyl;

R⁷ and R^(7′) are, independently, hydrogen or alkyl, or R⁷ and R^(7′)together are —(CH₂)_(p)—, wherein p is 4 to 8;

R⁶ and R^(6′) are, independently, hydrogen or alkyl, or R⁶ and R^(6′)together are (CH₂)₂NR¹²(CH₂)₂, wherein R¹² is hydrogen, —C(═N)CH₃ orC(═NH)—NH₂;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s);    -   (iii) —Y-A₂-Y—R², and R² is hydrogen, a polar group (PL), or a        non-polar group (NPL); or    -   (iv) —Y-A¹ and R² is —X-A′, wherein A′ is aryl or heteroaryl and        is optionally substituted with one or more polar (PL) group(s),        one or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (v) R¹ and R² are, independently, a polar group (PL) or a        non-polar group (NPL); or    -   (vi) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))—V

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 20,

and an ophthalmically acceptable excipient.4) The composition of 1) or 2), wherein the oligomer has Formula IIa:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  (IIa)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, O, S, or —N(R⁸)N(R⁸)—;

Y is C═O, C═S, or O═S═O;

R⁸ is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is a polar group (PL) or a non-polar group (NPL);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V,

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2.

5) The composition of any one of 1), 2), and 4), wherein:

X is NR⁸;

Y is C═O;

R⁸ is hydrogen or (C₁-C₄)alkyl;

A₁ and A₂ are, independently, optionally substituted phenylene oroptionally substituted pyrimidinylene, wherein A₁ is substituted withone or more polar (PL) group(s) and one or more non-polar (NPL)group(s), and A₂ is substituted with one or more polar (PL) group(s) oris unsubstituted;

R¹ is a polar group (PL);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R⁴ and R^(4′) are, independently, selected from hydrogen and alkyloptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, NR³, and —C(═O)—;

pNPL is 0 to 6;

q1NPL and q2NPL are 0;

PL is a polar group—(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NR⁵, and —C(═O)—;

V is selected from amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH2CH2NH2)₂, diazamino, amidino, and guanidino,any of which is optionally substituted with one or more of amino, halo,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, and lower acylamino;

pPL is 0 to 8; and

q1PL and q2PL are 0.

6) The composition of any one of 1), 2), 4), and 5), wherein:

A₁ is phenylene substituted with one (PL) group and one non-polar (NPL)group;

A₂ is unsubstituted pyrimidinylene or pyrimidinylene substituted withone or two polar (PL) group(s);

NPL is R^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substitutedwith one or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6.

7) The composition of any one of 1), 2), 4), and 5), wherein:

A₁ is phenylene substituted with one (PL) group and one non-polar (NPL)group;

A₂ is unsubstituted phenylene or phenylene substituted with one or twopolar (PL) group(s);

NPL is R^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substitutedwith one or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6.

8) The composition of any one of 1), 2), 4), 5), and 6), wherein theoligomer is

or a salt or solvate thereof9) The composition of any one of 1), 2), and 4), wherein the oligomer is

or a salt or solvate thereof10) The composition of any one of 1), 2), 4), 5), 6), and 8), whereinthe oligomer is

or a salt or solvate thereof11) The composition of any one of 1), 2), 4), 5), 6), and 8), whereinthe oligomer is

or a salt or solvate thereof12) The composition of any one of 1), 2), 4), 5), 6), and 8), whereinthe oligomer is

or a salt or solvate thereof13) The composition of any one of 1), 2), 4), 5), 6), and 8), whereinthe oligomer is

or a salt or solvate thereof14) The composition of any one of 1), 2), 4), 5), 6), and 8), whereinthe oligomer is

or a salt or solvate thereof15) The composition of any one of 1), 2), 4), and 5), wherein theoligomer is

or a salt or solvate thereof16) The composition of any one of 1), 2), 4), 5), and 15), wherein theoligomer is

or a salt or solvate thereof17) An ophthalmic composition, comprising an effective amount of anantimicrobial oligomer of Formula IV:

R¹—[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  (IV)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —NR⁸NR⁸—, C═O, or O;

Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O;

R⁸ is hydrogen or alkyl;

Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y-A₂-Y—R¹, wherein A₁ and A₂ are as defined        above, and each of which is optionally substituted with one or        more polar (PL) group(s), one or more non-polar (NPL) group(s),        or a combination of one or more polar (PL) group(s) and one or        more non-polar (NPL) group(s); or    -   (iii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (iv) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y-A′-Y—R¹, wherein A₁ is as defined above,        A′ is aryl or heteroaryl, and each of A₁ and A′ is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); or    -   (v) —Z—Y-A¹ and R² is hydrogen, a polar group (PL), or a        non-polar group (NPL), wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vi) —Z—Y-A′, and R² is —X-A″, wherein A′ and A″ are,        independently, aryl or heteroaryl, and each of A and A″ is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vii) R¹ and R² are, independently, a polar group (PL) or a        non-polar group (NPL); or    -   (viii) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 20;

and an ophthalmically acceptable excipient.18) The composition of 17), wherein the oligomer has Formula IVa,Formula IVb, or Formula IVc:

R¹—X-A₁-X—Z—Y-A₂-Y—R²  (IVa)

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—R²  (IVb)

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—Z—Y-A₂-Y—R²  (IVc)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —NR⁸NR⁸—, C═O, or O;

Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O;

R⁸ is hydrogen or alkyl;

Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is hydrogen, a polar group (PL), or a non-polar group (NPL);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2.

19) An ophthalmic composition, comprising an effective amount of anantimicrobial oligomer of Formula V:

R¹—[-A₁-W-A₂-W-]_(m)—R²  (V)

or an acceptable salt or solvate thereof,wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

(i) A₁ and A₂ are, independently, optionally substituted with one ormore polar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or

(ii) one of A₁ or A₂ is as defined above and is optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s); and the other of A₁ or A₂ is the group—C≡C(CH₂)_(p)C≡C—, wherein p is 0 to 8, and the —(CH₂)_(p)— alkylenechain is optionally substituted with one or more amino or hydroxylgroups;

W is absent, or represents —CH₂—, —CH₂—CH₂—, —CH═CH—, or —C≡C—;

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-W-A₂-R¹, wherein each of A₁ and A₂ is as defined        above and is optionally substituted with one or more polar (PL)        group(s), one or more non-polar (NPL) group(s), or a combination        of one or more polar (PL) group(s) and one or more non-polar        (NPL) group(s); or    -   (iii) A′-W— and R² is -A₁-W-A′, wherein A′ is aryl or        heteroaryl, either of which is optionally substituted with one        or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (iv) A′-W— and R² is -A′, wherein A′ is aryl or heteroaryl,        either of which is optionally substituted with one or more polar        (PL) group(s), one or more non-polar (NPL) groups(s), or a        combination of one or more polar (PL) group(s) and one or more        non-polar (NPL) group(s); or    -   (iv) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N— and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH²)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio,lower acylamino, or benzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0 to 2; and

m is 1 to about 25;

and an ophthalmically acceptable excipient.20) The composition of 19), wherein the oligomer has Formula Va:

R¹-A₁-W-A₂-W-A₁-R²  (Va)

or an acceptable salt or solvate thereof,wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

-   -   (i) A₁ and A₂ are, independently, optionally substituted with        one or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (ii) one of A₁ or A₂ is as defined above and is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); and the        other of A₁ or A₂ is the group —C≡C(CH₂)_(p)C≡C—, wherein p is 0        to 8, and the —(CH₂)_(p)— alkylene chain is optionally        substituted with one or more amino or hydroxyl groups;

W is —C≡C—;

R¹ is hydrogen, a polar group (PL), a non-polar group (NPL), or —W-A′,wherein A′ is aryl or heteroaryl, either of which is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH²)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴;

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³—O—, —R³—S—, —S—C═N—, and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the alkylene chain —(CH²)_(pNPL)— is optionally substituted with one ormore alkyl, amino or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)—NR^(5′))—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio,lower acylamino, or benzyloxycarbonyl;

the alkylene chain —(CH₂)_(pPL)— is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0 to 2.

21) The composition of 19) or 20), wherein

A₁ and A₂ are, independently, optionally substituted m-phenylene,wherein A₁ is optionally substituted with two polar (PL) groups, and A₂is unsubstituted;

R¹ is a polar group;

PL is independently halo or—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR⁵)_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NR⁵, and —C(═O)—;

V is selected from amino, amidino, and guanidino, any of which isoptionally substituted with one or more of amino, halo, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkylhio, and lower acylamino;

pPL is 0 to 8; and

q1PL and q2PL are 0.

22) The composition of any one of 19) to 21), wherein:

R¹ is halo;

PL is or —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is absent;

V is selected from amino, amidino, and guanidino, any of which isoptionally substituted with one or more of amino and halo; and

pPL is 0 to 6.

23) The composition of any one of 19) to 21), wherein the oligomer isone of

or a salt or solvate thereof24) The composition of any one of 19) to 21), wherein the oligomer is

25) An ophthalmic composition, comprising an effective amount of anantimicrobial random copolymer of Formula VI:

A-(B)_(n1)-(D)_(m1)-H  (VI)

or an acceptable salt or solvate thereof,wherein:

A is the residue of a chain transfer agent;

B is —[CH₂—C(R¹¹)(B₁₁)]—, wherein B₁₁ is —X₁₁—Y₁₁—Z₁₁, wherein

X₁₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₁₁ is absent;

Y₁₁ is O, NH, or optionally substituted C₁₋₆ alkylene; or Y₁₁ is absent;

Z₁₁ is —Z_(11A)-Z_(11B), wherein Z_(11A) is alkylene, arylene, orheteroarylene, any of which is optionally substituted; or Z_(11A) isabsent; and Z_(11B) is -guanidino, -amidino, —N(R³)(R⁴), or—N⁺(R³)(R⁴)(R⁵), wherein R³, R⁴, and R⁵ are, independently, hydrogen,alkyl, aminoalkyl, aryl, heteroaryl, heterocyclic, or aralkyl; or

Z₁₁ is pyridinium

or phosphonium

wherein R⁸¹, R⁹¹¹, R⁹²¹, and R⁹³¹ are, independently, hydrogen or alkyl;

R¹¹ is hydrogen or C₁₋₄ alkyl;

D is —[CH₂—C(R²¹)(D₂₁)]—, wherein D₂₁ is —X₂₁—Y₂₁—Z₂₁, wherein

X₂₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₂₁ is absent;

Y₂₁ is O, NH, or optionally substituted C₁₋₆ alkylene, or Y₂₁ is absent;

Z₂₁ is alkyl, cycloalkyl, alkoxy, aryl, or aralkyl, any of which isoptionally substituted;

R²¹ is hydrogen or C₁₋₄ alkyl;

m₁, the mole fraction of D monomer, is about 0.1 to about 0.9; and

n₁, the mole fraction of B monomer, is 1-m₁;

wherein the copolymer is a random copolymer of B and D monomers, and

wherein the copolymer has a degree of polymerization of about 5 to about50; and an ophthalmically acceptable excipient.

26) The composition of 25), wherein:

A is C₁₋₄ alkoxycarbonyl(C₁₋₄alkylthio;

X₁₁ and X₂₁ are carbonyl;

Y₁₁ and Y₂₁ are O;

Z₁₁ is —Z_(11A)-Z_(11B), wherein Z_(11A) is C₁₋₆ alkylene optionallysubstituted with C₁₋₄ alkyl) or aryl; and Z_(11B) is —N(R³¹)(R⁴¹) or—N⁺(R³¹)(R⁴¹)(R⁵¹), wherein R³¹, R⁴¹, and R⁵¹ are independently hydrogenC₁₋₄ alkyl;

Z₂₁ is C₁₋₆ alkyl, C₁₋₆ aryl, or C₁₋₆ ar(C₁₋₄alkyl; and

R¹¹ and R²¹ are, independently, hydrogen or methyl;

m₁ is about 0.35 to about 0.60; and

wherein the copolymer has a degree of polymerization of about 5 to about10.

27) An antimicrobial ophthalmic composition, the composition comprising:(a) an antimicrobial oligomer of Formula IIa:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  (IIa)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, O, S, or —N(R⁸)N(R⁸)—;

Y is C═O, C═S, or O═S═O;

R⁸ is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is a polar group (PL) or a non-polar group (NPL);

R² is R¹;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, anyof which is optionally substituted with one or more alkyl or halogroups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle and heteroaryl, any of which is optionally substitutedwith one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2;

or a pharmaceutically acceptable salt or solvate thereof, in an amounteffective for treatment and/or prophylaxis of a microbial infection ofan eye of an animal; and

(b) an ophthalmically acceptable excipient,

wherein the composition is suitable for administration to one or moretissues of the eye.28) The composition of 27), wherein:

A₁ is m-phenylene substituted with one (PL) group and one non-polar(NPL) group;

A₂ is unsubstituted m-pyrimidinylene or m-pyrimidinylene substitutedwith one or two polar (PL) group(s);

NPL is R^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substitutedwith one or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6.

29) The composition of 27), wherein:

A₁ is m-phenylene substituted with one (PL) group and one non-polar(NPL) group;

A₂ is unsubstituted m-phenylene or m-phenylene substituted with one ortwo polar (PL) group(s);

NPL is R⁴, wherein R^(4′) is (C₁-C₆)alkyl optionally substituted withone or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6.

30) The composition of 27) or 28), wherein the oligomer is one of

or a salt or solvate thereof31) The composition of 27) or 29), wherein the oligomer is one of

or a salt or solvate thereof.32) An ophthalmic composition for use in treatment or prevention of amicrobial infection in an eye of an animal, wherein compositioncomprises the antimicrobial oligomer of Formula I of 1) in an amounteffective to treat or prevent the infection when the composition isadministered to one or more tissues of the eye.33) An ophthalmic composition for use in treatment or prevention of amicrobial infection in an eye of an animal, wherein the compositioncomprises the antimicrobial oligomer of Formula II of 3) in an amounteffective to treat or prevent the infection when the composition isadministered to one or more tissues of the eye.34) An ophthalmic composition for use in treatment or prevention of amicrobial infection in an eye of an animal, wherein the compositioncomprises the antimicrobial oligomer of Formula IV of 17) in an amounteffective to treat or prevent the infection when the composition isadministered to one or more tissues of the eye.35) An ophthalmic composition for use in treatment or prevention of amicrobial infection in an eye of an animal, wherein the compositioncomprises the antimicrobial oligomer of Formula V of 19) in an amounteffective to treat or prevent the infection when the composition isadministered to one or more tissues of the eye.36) An ophthalmic composition for use in treatment or prevention of amicrobial infection in an eye of an animal, wherein the compositioncomprises the antimicrobial oligomer of Formula VI of 25) in an amounteffective to treat or prevent the infection when the composition isadministered to one or more tissues of the eye.37) The composition of any one of 1) to 36), wherein the composition issuitable for topical administration to one or more tissues of an eye ofan animal.38) The composition of any one of 1) to 36), wherein the composition isin a form selected from a solution, a suspension, an emulsion, a gel, anointment, and a solid article suitable for ocular implant.39) The composition of 38), wherein the oligomer is present in thecomposition at a concentration of about 0.01% to about 20% by weight.40) The composition of any one of 1) to 31), wherein the ophthalmicallyacceptable excipient is selected from a preservative, a stabilizer, anantioxidant, and a viscosity-enhancing agent, or any combinationthereof.41) The composition of 40), wherein the preservative is selected from aphenylmercuric salt, thimerosal, stabilized chlorine dioxide, quaternaryammonium compound, imidazolidinyl urea, paraben, phenoxyethanol,chlorophenoxyethanol, phenoxypropanol, chlorobutanol, chlorocresol,phenylethyl alcohol, and sorbic acid or a salt thereof, or anycombination thereof42) The composition of 40), wherein the antioxidant is selected fromascorbic acid, sodium metabisulfite, sodium bisulfite, andacetylcysteine.43) The composition of 40), wherein the stabilizer is a chelating agent.44) The composition of 43), wherein the chelating agent is disodium EDTA(disodium edetate).45) The composition of 40), wherein the viscosity-enhancing agent isselected from methylcellulose, hydroxypropylmethyl cellulose, polyvinylalcohol, and glycerol.46) The composition of 37), wherein the composition further comprises anadditional ophthalmically acceptable excipient.47) The composition of 46), wherein the additional ophthalmicallyacceptable excipient is selected from a buffering agent, a solubilizingagent, a surfactant, a lubricating agent, and an ophthalmicallyacceptable salt, or any combination thereof48) The composition of 37), wherein the composition further comprises anadditional medicament.49) The composition of 48), wherein the additional medicament isselected from an anti-inflammatory agent, an antimicrobial agent, ananesthetic agent, and an anti-allergic agent.50) The composition of 49), wherein the additional medicament is asteroidal anti-inflammatory agent.51) The composition of 50), wherein the steroidal anti-inflammatoryagent is a glucocorticoid.52) The composition of 50), wherein the steroidal anti-inflammatoryagent is selected from dexamethasone, rimexolone, prednisolone,fluorometholone, and hydrocortisone.53) The composition of 49), wherein the additional medicament is anantimicrobial agent.54) The composition of 53), wherein the antimicrobial agent is selectedfrom an anti-bacterial agent, an anti-fungal agent, and an anti-viralagent.55) A method of treating or preventing a microbial infection in an eyeof an animal, said method comprising administering to an eye of ananimal in need of said treating or preventing an effective amount of anophthalmic composition of any one of 1) to 36).56) The method of 55), wherein the ophthalmic composition is in a formselected from a solution, a suspension, an emulsion, a gel, an ointment,and a solid article suitable for ocular implant.57) The method of 55), wherein the composition is administered 2 to 4times daily.58) The method of 55), wherein the oligomer is present in thecomposition at a concentration of about 0.01% to about 20% by weight59) The method of 55), wherein the microbial infection is a bacterialinfection.60) The method of 59), wherein the bacterial infection is caused byStaphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium,Moraxella, Haemophilus, Serratia, Pseudomonas or Neisseria spp.61) The method of 55), wherein the microbial infection is a fungalinfection.62) The method of 61), wherein the fungal infection is caused byAspergillus or Fusarium spp.63) The method of 55), wherein the microbial infection is a viralinfection.64) The method of 63), wherein the viral infection is caused by a herpesvirus.65) The method of 55), wherein the infection is selected from bacterialkeratitis, bacterial conjunctivitis, and corneal ulcer.66) A method for treating or preventing a microbial infection in an eyeof an animal by administering to one or more tissues of the eye anantimicrobial ophthalmic composition, the composition comprising anantimicrobial oligomer of Formula I of 1) in an amount effective totreat or prevent the infection.67) A method for treating or preventing a microbial infection in an eyeof an animal by administering to one or more tissues of the eye anantimicrobial ophthalmic composition, the composition comprising anantimicrobial oligomer of Formula II of 3) in an amount effective totreat or prevent the infection.68) A method for treating or preventing a microbial infection in an eyeof an animal by administering to one or more tissues of the eye anantimicrobial ophthalmic composition, the composition comprising anantimicrobial oligomer of Formula IV of 17) in an amount effective totreat or prevent the infection.69) A method for treating or preventing a microbial infection in an eyeof an animal by administering to one or more tissues of the eye anantimicrobial ophthalmic composition, the composition comprising anantimicrobial oligomer of Formula V of 19) in an amount effective totreat or prevent the infection.70) A method for treating or preventing a microbial infection in an eyeof an animal by administering to one or more tissues of the eye anantimicrobial ophthalmic composition, the composition comprisingemploying an antimicrobial oligomer of Formula VI of 25) in an amounteffective to treat or prevent the infection.71) The method of any one of 66) to 70), wherein the antimicrobialophthalmic composition is administered topically to one or more tissuesof the eye of the animal.72) The method of 71), wherein the ophthalmic composition is in a formselected from a solution, a suspension, an emulsion, a gel, an ointment,and a solid article suitable for ocular implant.73) The method of 71), wherein the composition is administered 2 to 4times daily.74) The method of 71), wherein the oliogmer is present in thecomposition at a concentration of about 0.01% to about 20% by weight.75) The method of 71), wherein the microbial infection is a bacterialinfection.76) The method of 75), wherein the bacterial infection is caused byStaphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium,Moraxella, Haemophilus, Serratia, Pseudomonas or Neisseria spp.77) The method of 71), wherein the microbial infection is a fungalinfection.78) The method of 77), wherein the fungal infection is caused byAspergillus or Fusarium spp.79) The method of 71), wherein the microbial infection is a viralinfection.80) The method of 79), wherein the viral infection is caused by a herpesvirus.81) The method of 71), wherein the infection is selected from bacterialkeratitis, bacterial conjunctivitis, and corneal ulcer.82) Use of a compound of 1) in the preparation of a medicament fortreating or preventing an ophthalmic and/or otic infection in an animal.

DESCRIPTION OF EMBODIMENTS

The present invention provides compositions of amphiphilic,antimicrobial polymers, and/or oligomers that can be used in thetreatment or prevention of ophthalmic and otic infections in humans andanimals. The present invention also provides methods of using thecompositions to treat or prevent ophthalmic and otic infections inhumans and animals.

The antimicrobial polymers and oligomers useful in the present inventionare polymers and oligomers of Formulae I, II, IV, V and VI:

R¹—[-X-A₁-Y—X-A₂-Y-]_(m)—R²  (I)

R¹—[-X-A₁-X—Y-A₂-Y-]_(m)—R²  (II)

R¹—[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  (IV)

R¹—[-A₁-W-A₂-W-]_(m)—R²  (V)

A-(B)_(n1)-(D)_(m1)-H  (VI)

or acceptable salts or solvates thereof, wherein R¹, R², A₁, A₂, A, B,D, X, Y, Z, W, m, ml, and n1 are as defined below.

The polymers and oligomers useful in the present invention are capableof adopting amphiphilic conformations that allow for the segregation ofpolar and nonpolar regions of the molecule into different spatialregions. This separation of charge, or facial amphiphilicity, forms thebasis for the anti-microbial activity observed for these polymers andoligomers, making them useful as anti-microbial agents. Use of thepolymers and oligomers of Formulae I, II, and IV generally asanti-microbial agents is described in US Published Patent Appl. No. US2006-0041023 A1 and U.S. Pat. No. 7,173,102. Use of the polymers andoligomers of Formula V generally as anti-microbial agents is describedin US Published Patent Appl. Nos. US 2004-0202639 A1 and US 2005-0287108A1. Use of the random copolymers of Formula VI generally asanti-microbial agents is described in US Published Patent Appl. No. US2006-0024264 A1.

The polymers and oligomers employed in the present invention wereoriginally designed to mimic the antimicrobial activities of hostdefense peptides, which were potentially exciting therapeutic agentsbecause of their broad spectrum of activity, rapid bacteriocidalactivity, and very low incidence of development of bacterial resistance,but which presented a number of significant pharmaceutical issues,including systemic toxicity and difficulty and expense of manufacturing,that severely hampered clinical progress in their use as therapeutics.

Many of the oligomers of Formulae I, II, and IV are significantlysmaller and easier to prepare than their naturally occurringcounterparts. They have the same mechanism of action as magainin (anaturally occurring host defense peptide) and are approximatelyequipotent and as broad in their spectrum of action as magainin.However, the non-peptidic polymers and oligomers of the presentinvention are significantly less toxic towards human erythrocytes, muchless expensive to prepare, and are expected to be much more stable invivo.

The present invention discloses ophthalmic and otic compositionscomprising anti-microbial, facially amphiphilic polymers and oligomers.Polymers are generally defined as synthetic compounds assembled frommonomer subunits that are polydisperse in molecular weight, and are mostcommonly prepared by one-pot synthetic procedures. The term “polymer” asused herein refers to a macromolecule comprising a plurality ofrepeating units or monomers. The term includes homopolymers, which areformed from a single type of monomer, and copolymers, which are formedfrom two or more different monomers. In copolymers, the monomers may bedistributed randomly (random copolymer), in alternating fashion(alternating copolymers), or in blocks (block copolymer). The polymersof the present invention are either homopolymers or alternatingcopolymers having about 2 monomer units to about 500 monomer units, withaverage molecular weights that range from about 300 Daltons to about1,000,000 Daltons, or from about 400 Daltons to about 120,000 Daltons.Preferred polymers are those having about 5 to about 100 monomer units,with average molecular weights that range from about 1,000 Daltons toabout 25,000 Daltons.

The term “oligomer” as used herein refers to a homogenous polymer with adefined sequence and molecular weight. Modern methods of solid phaseorganic chemistry have allowed the synthesis of homodisperse,sequence-specific oligomers with molecular weights approaching 5,000Daltons. An oligomer, in contrast to a polymer, has a defined sequenceand molecular weight and is usually synthesized either by solid phasetechniques or by step-wise solution chemistry and purified tohomogeneity. Oligomers of the present invention are those having about 2monomer units to about 25 monomer units, with molecular weights thatrange from about 300 Daltons to about 6,000 Daltons. Preferred oligomersare those having about 2 monomer units to about 10 monomer units, withmolecular weights that range from about 300 Daltons to about 2,500Daltons.

For the ophthalmic and otic compositions described herein, oligomers arethe preferred species because of their defined size and structure.

The term “polymer backbone,” “oligomer backbone,” or “backbone” as usedherein refers to that portion of the polymer or oligomer which is acontinuous chain comprising the bonds formed between monomers uponpolymerization. The composition of the polymer or oligomer backbone canbe described in terms of the identity of the monomers from which it isformed without regard to the composition of branches, or side chains, ofthe polymer or oligomer backbone.

The term “polymer side chain,” “oligomer side chain,” or “side chain”refers to portions of the monomer which, following polymerization, formsan extension of the polymer or oligomer backbone. In homopolymers andhomooligomers, all the side chains are derived from the same monomer.

The term “amphiphilic” as used herein describes a three-dimensionalstructure having discrete hydrophobic and hydrophilic regions. Anamphiphilic polymer requires the presence of both hydrophobic andhydrophilic elements along the polymer backbone. The presence ofhydrophobic and hydrophilic groups is a necessary, but not sufficient,condition to produce an amphiphilic molecule, polymer, or oligomer.

The term “facially amphiphilic” or “facial amphiphilicity” as usedherein describes polymers or oligomers with polar (hydrophilic) andnonpolar (hydrophobic) side chains that adopt conformation(s) leading tosegregation of polar and nonpolar side chains to opposite faces orseparate regions of the structure or molecule.

The phrase “groups with chemically nonequivalent termini” refers tofunctional groups such as esters amides, sulfonamides, andN-hydroxyoximes where reversing the orientation of the substituents, forexample, R¹C(═O)OR² versus R¹O(O═)CR², produces unique chemicalentities.

The present invention is directed to antimicrobial ophthalmic and oticcompositions comprising one or more of the polymers or oligomersdisclosed herein, as defined below, and an ophthalmically acceptableexcipient.

Thus, in some aspects of the present invention, the ophthalmic or oticcomposition comprises a polymer or oligomer of Formula I:

R¹—[-X-A₁-Y—X-A₂-Y-]_(m)—R²  (I)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —N(R⁸)N(R⁸)—, O, or S;

Y is C═O, C═S, O═S═O, or —C(═O)C(═O)—;

R⁸ is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

A₁ is optionally substituted arylene or optionally substitutedheteroarylene and A₂ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein qis 1 to 7, wherein A₁ and A₂ are, independently, optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s); or

A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and A₁ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein qis 1 to 7, wherein A₁ and A₂ are, independently, optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s);

R¹ is

(i) hydrogen, a polar (PL) group, or a non-polar (NPL) group, and R² is—X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a polar (PL) group, or a non-polar(NPL) group; or

(ii) R¹ and R² are, independently, hydrogen, a polar (PL) group, or anon-polar (NPL) group; or

(iii) R¹ and R² together are a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from the groupconsisting of hydrogen, alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, anyof which is optionally substituted with one or more alkyl or halogroups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V,

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl, wherein p is 1 to 4;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are independently 0, 1 or 2; and

m is 1 to about 500;

and an ophthalmically or optically acceptable excipient.

US Patent Application Publ. No. US 2006-0041023 A1 disclosesantimicrobial polymers and oligomers of Formula I that can be used inthe compositions of the present invention.

For example, oligomers of Formula I preferred for use in the ophthalmicand otic compositions of the present invention are those wherein m is 1to about 25, 1 to about 20, 1 to 10, 2 to 8, 2 to 6, 2 to 5, or 4 or 5.

Preferred oligomers of Formula I are also those wherein X is NR⁸, O, or—N(R⁸)N(R⁸)—, and R⁸ is hydrogen or C₁-C₆ alkyl. Especially preferredare those polymers and oligomers wherein X is NR⁸ and Y is C═O. Forexample, oligomers of Formula I wherein X is NH and Y is C═O areespecially preferred.

Also preferred are those oligomers of Formula I wherein A₁ or A₂ are,independently, optionally substituted o-, m-, or p-phenylene. Thoseoligomers wherein A₁ or A₂ are optionally substituted m-phenylene areespecially preferred.

Preferred oligomers of Formula I are also those wherein one of A₁ and A₂is substituted arylene and the other of A₁ and A₂ is —(CH₂)_(q)—,wherein q is 1 or 2, wherein one of A₁ and A₂ is substituted with one ortwo polar (PL) group(s), and the other of A₁ and A₂ is substituted withone or two non-polar (NPL) group(s).

Preferred are oligomers of Formula I wherein (i) R¹ is hydrogen, a polar(PL) group, or a non-polar (NPL) group, and R² is —X-A₁-Y—R¹¹, whereinR¹¹ is hydrogen, a polar (PL) group, or a non-polar (NPL) group.Especially preferred are oligomers of Formula I wherein R¹ is hydrogen,R² is —X-A₁-Y—R¹¹, and R¹¹ is a polar (PL) group, for example, amino.

In some embodiments, preferred oligomers of Formula I are those whereinR¹ and R² are, independently, hydrogen, a polar (PL) group, or anon-polar (NPL) group. Especially preferred are oligomers of Formula Iwherein R¹ is hydrogen, and R² is a polar group, for example, amino.

In other aspects of the invention, preferred oligomers of Formula I arethose wherein NPL is—(NR^(3′))_(q1NPL)—U^(NPL)—(CH²)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′), andR³, R^(3′), R^(3″), R^(4′), U^(NPL), pNPL, q1NPL, and q2NPL are asdefined above. Especially preferred are those oligomers of Formula Iwherein q1NPL and q2NPL are 0, so that NPL is—U^(NPL)—(CH₂)_(pNPL)—R^(4′).

Preferred values for each of R³, R^(3′), and R^(3″) are hydrogen, C₁-C₆alkyl, and C₁-C₆ alkoxy. Hydrogen is an especially preferred value forR³, R^(3′), and R^(3″).

Preferred values of R^(4′) are hydrogen, C₁-C₁₀ alkyl, C₃-C₁₈ branchedalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl,especially phenyl, and heteroaryl, any of which is optionallysubstituted with one or more C₁-C₆ alkyl or halo groups. Especiallypreferred values of R^(4′) are C₁-C₁₀ alkyl and C₃-C₁₈ branched alkyl.Suitable C₁-C₁₀ alkyl and C₃-C₁₈ branched alkyl groups are methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, andisopentyl.

Preferred values of U^(NPL) are NH, —C(═O)—, —C(═O)O—, O, and S.Especially preferred values are NH, —C(═O)—, O, and S, or NH, O, and S.Especially preferred oligomers of Formula I also are those whereinU^(NPL) is absent.

Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 areespecially preferred, with values of pNPL of 0 to 2 most preferred.

Preferred values of q1NPL and q2NPL are 0 or 1. Values of q1NPL andq2NPL of 0 or 1 are especially preferred, with a value of 0 being themost preferred for each of q1NPL and q2NPL.

In preferred ophthalmic and otic compositions, oligomers of Formula Iwherein the —(CH₂)_(pNPL)— alkylene chain in NPL is unsubstituted orsubstituted with one or more alkyl groups are preferred. More preferredare those oligomers of Formula I wherein the —(CH₂)_(pNPL)— alkylenechain in NPL is unsubstituted.

An especially preferred value of NPL for the polymers and oligomers ofFormula I is C₁-C₆ alkyl or aryl C₁-C₆ alkyl. Examples of preferredvalues for NPL are n-propyl, isopropyl, n-butyl, tert-butyl, and benzyl.

In some embodiments of the invention, preferred oligomers of Formula Iare those wherein PL is—(NR^(5′))_(q1PL)—U^(PL)(CH²)_(pPL)—(NR^(5″))_(q2PL)—V, and R⁵, R^(5′),R^(5″), V, U^(PL), pPL, q1PL, and q2PL are as defined above. Especiallypreferred are those oligomers of Formula I wherein q1PL and q2PL are 0,so that PL is —U^(PL)—(CH₂)_(pPL)—V.

Preferred values for R⁵, R^(5′), and R^(5″) are hydrogen, C₁-C₆ alkyl,and C₁-C₆ alkoxy. Hydrogen is an especially preferred value for each ofR⁵, R^(5′), and R^(5″).

Preferred values of U^(PL) are O, S, NH, —C(═O)O—, and —C(═O).Especially preferred values are NH, —C(═O)—, O, and S, or NH, O, and S.Preferred oligomers of Formula I are also those wherein U^(PL) isabsent.

Preferred values of V are amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino,guanidino, guanyl, and semicarbazone, preferably any of which isoptionally substituted with one or more of amino, halo, cyano, nitro,hydroxy, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl.

Especially preferred values of V are amino, C₁-C₆ alkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino,and guanidino. Values of V that are most preferred are amino andguanidino.

Preferred values of pPL are 0 to 6, with values of pPL of 2 to 5especially preferred.

Preferred values of q1PL and q2PL are 0 or 1. Values of q1PL and q2PL of0 or 1 are especially preferred, with a value of 0 being especiallypreferred for each of g1 PL and q2PL.

In preferred ophthalmic compositions, oligomers of Formula I wherein the—(CH₂)_(pPL)— alkylene chain in PL is optionally substituted with one ormore amino groups are preferred.

Thus, preferred ophthalmic or otic compositions comprise an oligomer ofFormula I, or an acceptable salt or solvate thereof, wherein:

X is NR⁸, Y is C═O, and R⁸ is hydrogen;

A₁ is optionally substituted o-, m-, or p-phenylene and A₂ is—(CH₂)_(q)—, wherein q is 1, and wherein one of A₁ and A₂ is substitutedwith one or two polar (PL) group(s), and the other of A₁ and A₂ issubstituted with one or two non-polar (NPL) group(s); or

A₂ is optionally substituted o-, m-, or p-phenylene and A₁ is—(CH₂)_(q)—, wherein q is 1, and wherein one of A₁ and A₂ is substitutedwith one or two polar (PL) group(s), and the other of A₁ and A₂ issubstituted with one or two non-polar (NPL) group(s);

R¹ and R² are, independently, hydrogen, a polar (PL) group, or anon-polar (NPL) group;

NPL is —(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴,wherein:

R^(4′) is selected from C₁-C₁₀ alkyl, C₃-C₁₈ branched alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, and C₆-C₁₀ aryl, any of which is optionallysubstituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from NH, —C(═O)—, O, and S;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino groups;

pNPL is 0 to 8;

q1NPL and q2NPL are 0;

PL is —(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NH, and —C(═O);

V is selected from amino, C₁-C₆ alkylamino, —NH(CH₂)_(p)NH₂ wherein p is1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, and guanidino;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino groups;

pPL is 0 to 8;

q1PL and q2PL are 0; and

m is 4 or 5;

and an ophthalmically or otically acceptable excipient.

Preferred ophthalmic or otic compositions also comprise an oligomer ofFormula I, or an acceptable salt or solvate thereof, wherein:

X is NR⁸, Y is C═O, and R⁸ is hydrogen;

A₁ is optionally substituted o-, m-, or p-phenylene and A₂ is—(CH₂)_(q)—, wherein q is 1 or 2, and wherein one of A₁ and A₂ issubstituted with one polar (PL) group, and the other of A₁ and A₂ issubstituted with one non-polar (NPL) group; or

A₂ is optionally substituted o-, m-, or p-phenylene and A₁ is—(CH₂)_(q)—, wherein q is 1 or 2, and wherein one of A₁ and A₂ issubstituted with one polar (PL) group, and the other of A₁ and A₂ issubstituted with one non-polar (NPL) group;

R¹ and R² are, independently, hydrogen or amino;

NPL is —U^(NPL)—(CH₂)_(pNPL)—R^(4′), wherein:

R^(4′) is selected from C₁-C₁₀ alkyl and C₃-C₁₈ branched alkyl, any ofwhich is optionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from NH, —C(═O)—, O, and S;

the —(CH²)_(pNPL)— alkylene chain is unsubstituted;

pNPL is 0 to 8;

q1NPL and q2NPL are 0;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is absent or selected from O, S, NH, and —C(═O);

V is selected from amino, C₁-C₆ alkylamino, —NH(CH₂)_(p)NH₂ wherein p is1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, and guanidino;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino groups;

pPL is 0 to 8;

q1PL and q2PL are 0; and

m is 4 or 5;

and an ophthalmically or otically acceptable excipient.

In other aspects of the present invention, the ophthalmic or oticcomposition comprises a polymer or oligomer of Formula II:

R¹—[—X-A₁-X—Y-A₂-Y-]_(m)—R²  (II)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, O, S, —N(R⁸)N(R⁸)—, —N(R⁸)—(N═N)—, —(N═N)—N(R⁸)—,—C(R⁷R^(7′))NR⁸—, —C(R⁷R^(7′))O—, or —C(R⁷R^(7′))S—; and

Y is C═O, C═S, O═S═O, —C(═O)C(═O)—, C(R⁶R^(6′))C═O or C(R⁶R^(6′))C═S; or

X and Y are taken together to be pyromellitic diimide;

wherein

R⁸ is hydrogen or alkyl;

R⁷ and R^(7′) are, independently, hydrogen or alkyl, or

R⁷ and R^(7′) together are —(CH₂)_(p)—, wherein p is 4 to 8; and

R⁶ and R^(6′) are, independently, hydrogen or alkyl, or

R⁶ and R^(6′) together are (CH₂)₂NR¹²(CH₂)₂, wherein R¹² is hydrogen,—C(═N)CH₃ or C(═NH)—NH₂;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s);    -   (iii) —Y-A₂-Y—R², and R² is hydrogen, a polar group (PL), or a        non-polar group (NPL); or    -   (iv) —Y-A¹ and R² is —X-A′, wherein A′ is aryl or heteroaryl and        is optionally substituted with one or more polar (PL) group(s),        one or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (v) R¹ and R² are, independently, a polar group (PL) or a        non-polar group (NPL); or    -   (vi) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(qNPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are independently selected from hydrogen, alkyl,and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino, or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N— and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from the group consisting of nitro, cyano, amino, hydroxy,alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein pis 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl,semicarbazone, aryl, heterocycle, and heteroaryl, any of which isoptionally substituted with one or more of amino, halo, cyano, nitro,hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino,guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, loweracylamino, or benzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 500; and an ophthalmically or otically acceptableexcipient.

US Patent Publ. No. US 2006-0041023 A1 discloses antimicrobial polymersand oligomers of Formula II that can be used in the compositions of thepresent invention. For example, oligomers of Formula II that arepreferred for use in the ophthalmic or otic compositions of the presentinvention are those wherein m is 1 to about 25, 1 to about 20, 1 toabout 10, 1 to about 5, or 1, 2, or 3.

Thus, preferred ophthalmic or otic compositions of the present inventionalso comprise an oligomer of Formula IIa:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  (IIa)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, O, S, or —N(R⁸)N(R⁸)—; and Y is C═O, C═S, or O═S═O; wherein R⁸is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is a polar group (PL) or a non-polar group (NPL); and R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino, or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(qin)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2;

and an ophthalmically or otically acceptable excipient.

Preferred oligomers of Formula IIa for use in the ophthalmic or oticcompositions of the present invention are those wherein X is NR⁸ and Yis C═O. For example, oligomers of Formula IIa wherein X is NH and Y isC═O are especially preferred.

Preferred also are those oligomers of Formula IIa wherein A₁ and A₂ areindependently optionally substituted o-, m-, or p-phenylene. Thoseoligomers wherein A₁ and A₂ are optionally substituted m-phenylene areespecially preferred.

Also preferred are those oligomers of Formula IIa wherein one of A₁ andA₂ is o-, m-, or p-phenylene, and the other of A₁ and A₂ is o-, m-, orp-heteroarylene. Preferred heteroarylene groups include, but are notlimited to, pyridinylene, pyrimidinylene, and pyrazinylene. Anespecially preferred heteroarylene group is pyrimidinylene, inparticular, m-pyrimidinylene.

Also preferred are oligomers of Formula IIa wherein A₁ and A₂ are,independently, optionally substituted arylene or optionally substitutedheteroarylene, and (i) one of A₁ and A₂ is substituted with one or morepolar (PL) group(s) and one or more nonpolar (NPL) group(s) and theother of A₁ and A₂ is unsubstituted; or (ii) one of A₁ and A₂ issubstituted with one or more polar (PL) group(s) and one or morenonpolar (NPL) group(s) and the other of A₁ and A₂ is substituted withone or more polar (PL) group(s). Especially preferred are oligomers inwhich either (i) one of A₁ and A₂ is substituted with one polar (PL)group and one nonpolar (NPL) group, and the other of A₁ and A₂ isunsubstituted, or (ii) one of A₁ and A₂ is substituted with one polar(PL) group and one nonpolar (NPL) group and the other of A₁ and A₂ issubstituted with one or two polar (PL) group(s), as defined above.

Preferred oligomers of Formula IIa are also those wherein R¹ is hydrogenor a polar group (PL). Especially preferred oligomers are those whereinR¹ is —(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, whereinR⁵, R^(5′), R^(5″), V, U^(PL), and pPL are as defined above, and q1PLand q2PL are each 0, so that especially preferred oligomers of FormulaIIa are those wherein R¹ is —U^(PL)—(CH₂)_(pPL)—V. Preferred R¹ polargroups are those wherein U^(PL) is absent or is O, S, NH, —C(═O)O—, or—C(═O); pPL is 0 to 6, especially 1 to 4; and V is amino, aminoalkyl,amidino, guanidino, aryl, or heteroaryl optionally substituted with oneor more amino, guanidino, amidino, or halo groups.

Preferred values for each of R³, R^(3′), and R^(3″) are hydrogen, C₁-C₆alkyl, and C₁-C₆ alkoxy. Hydrogen is an especially preferred value forR³, R^(3′), and R^(3″).

Preferred values of R^(4′) are hydrogen and alkyl optionally substitutedwith one or more alkyl or halo groups. More preferred values of R^(4′)are hydrogen, C₁-C₁₀ alkyl, C₃-C₁₈ branched alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, and C₆-C₁₀ aryl, especially phenyl. Especially preferredvalues of R^(4′) are C₁-C₁₀ alkyl and C₃-C₁₈ branched alkyl. SuitableC₁-C₁₀ alkyl and C₃-C₁₈ branched alkyl groups are methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, and n-pentyl.

Preferred oligomers of Formula IIa are those wherein U^(NPL) is absent.In other embodiments, preferred oligomers of Formula IIa are thosewherein U^(NPL) is O, S, NH, —C(═O)—, —C(═O)O—, —R³⁵—, or —R³O—.Especially preferred values of U^(NPL) are O, —C(═O)—, and —C(═O)O—.

Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 areespecially preferred, with values of pNPL of 0, 1 or 2 most preferred.

Preferred values of q1NPL and q2NPL are 0 or 1. Values of q1NPL andq2NPL of 0 or 1 are especially preferred, with a value of 0 being themost preferred for each of q1NPL and q2NPL.

In preferred oligomers of Formula IIa, the —(CH²)_(pNPL)— alkylene chainin NPL is unsubstituted or substituted with one or more alkyl groups.

An especially preferred value of NPL for oligomers of Formula II isC₁-C₆ alkyl optionally substituted with one or more halo groups.Examples of preferred values for NPL are n-propyl, isopropyl, n-butyl,tert-butyl, and trifluoromethyl.

Preferred oligomers of Formula IIa are those wherein PL is—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, and R⁵, R^(5′),R^(5″), V, U^(PL), pPL, q1PL and q2PL are as defined above.

Preferred values for R⁵, R^(5′), and R^(5″) are hydrogen, C₁-C₆ alkyl,and C₁-C₆ alkoxy. Hydrogen is an especially preferred value for each ofR⁵, R^(5′), and R^(5″).

Preferred values of U^(PL) are O, S, NR⁵, —C(═O)—, —C(═O)—N═N—NH—,—C(═O)—NH—N═N—, —N═N—NH—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —R⁵S—,and —R⁵⁰—, wherein R⁵ is hydrogen. Especially preferred values of U^(PL)are O, S, NH, —C(═O)O—, and —C(═O). Preferred oligomers of Formula IIaare also those wherein U^(PL) is absent.

Preferred values of V are nitro, cyano, amino, hydroxy, C₁-C₆ alkoxy,C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino,guanyl, semicarbazone, C₆-C₁₀ aryl, heterocycle, and heteroaryl, any ofwhich is optionally substituted with one or more of amino, halo, cyano,nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino,or benzyloxycarbonyl.

Suitable heteroaryl groups include indolyl, 3H-indolyl, 1H-isoindolyl,indazolyl, benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitableheterocycle groups include piperidinyl, piperazinyl, imidazolidinyl,pyrrolidinyl, pyrazolidinyl, and morpholinyl.

Values of V that are more preferred are amino, C₁-C₆ alkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino,and guanidino, preferably any of which is optionally substituted withone or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanyl, guanidino, oraminoalkoxy. Values of V that are most preferred are amino andguanidino.

Preferred values of pPL are 0 to 6; values of pPL of 0 to 4 areespecially preferred, with values of pPL of 2 to 4 especially preferred.

Preferred values of q1PL and q2PL are 0 or 1. Values of q1PL and q2PL of0 or 1 are especially preferred, with a value of 0 being especiallypreferred for each of g1 PL and q2PL.

In preferred polymers and oligomers of Formula IIa, the —(CH₂)_(pPL)—alkylene chain in PL is optionally substituted with one or more amino orhydroxy groups.

Thus, preferred ophthalmic or otic compositions comprise an oligomer ofFormula IIa, or an acceptable salt or solvate thereof, wherein:

X is NR⁸, and Y is C═O; wherein R⁸ is hydrogen or (C₁-C₄)alkyl;

A₁ and A₂ are, independently, optionally substituted phenylene oroptionally substituted pyrimidinylene, wherein A₁ is substituted withone or more polar (PL) group(s) and one or more non-polar (NPL)group(s), and A₂ is substituted with one or more polar (PL) group(s) oris unsubstituted;

R¹ is a polar group (PL); and R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R⁴ and R^(4′) are, independently, selected from hydrogen and alkyloptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, NR³, and —C(═O)—; pNPL is 0 to6;

q1NPL and q2NPL are, independently, 0;

PL is a polar group—(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NR⁵, and —C(═O)—;

V is selected from amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, and guanidino,any of which is optionally substituted with one or more of amino, halo,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, and lower acylamino;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0;

and an ophthalmically or otically acceptable excipient.

In some embodiments, preferred ophthalmic or otic compositions of thepresent invention comprise an oligomer of Formula IIa, or an acceptablesalt or solvate thereof, wherein:

A₁ is phenylene substituted with one (PL) group and one non-polar (NPL)group, and A₂ is unsubstituted pyrimidinylene or pyrimidinylenesubstituted with one or two polar (PL) group(s);

NPL is R^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substitutedwith one or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6;

and an ophthalmically or otically acceptable excipient.

Examples of oligomers of Formula IIa for use in the ophthalmic or oticcompositions of the present invention include

and ophthalmically or otically acceptable salts thereof.

In other embodiments, preferred ophthalmic or otic compositions comprisean oligomer of Formula IIa, or an acceptable salt or solvate thereof,wherein:

A₁ is phenylene substituted with one (PL) group and one non-polar (NPL)group, and A₂ is unsubstituted phenylene or phenylene substituted withone or two polar (PL) group(s);

NPL is R^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substitutedwith one or more halo groups;

PL is —U^(PL)—(CH₂)_(pPL)—V, wherein:

U^(PL) is O or S;

V is selected from amino, amidino, and guanidino; and

pPL is 0 to 6; and

an ophthalmically or otically acceptable excipient.

In some of these embodiments, preferred ophthalmic or otic compositionscomprise oligomers of Formula IIa wherein A₁ is phenylene substitutedwith one (PL) group and one non-polar (NPL) group, and A₂ is phenylenesubstituted with one or two polar (PL) group(s). Oligomers of FormulaIIa falling within the scope of these embodiments include to following:

and ophthalmically or otically acceptable salts thereof.

In other embodiments, preferred ophthalmic or otic compositions compriseoligomers wherein A₁ is phenylene substituted with one (PL) group andone non-polar (NPL) group, and A₂ is unsubstituted phenylene. Oligomersfalling within the scope of these embodiments include the following:

and ophthalmically or otically acceptable salts thereof.

In other aspects, the ophthalmic or otic compositions of the presentinvention comprise a polymer or oligomer of Formula IV:

R¹—[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  (IV)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —NR⁸NR⁸—, C═O, or O; Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O; and R⁸is hydrogen or alkyl;

Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y-A₂-Y—R¹, wherein A₁ and A₂ are as defined        above, and each of which is optionally substituted with one or        more polar (PL) group(s), one or more non-polar (NPL) group(s),        or a combination of one or more polar (PL) group(s) and one or        more non-polar (NPL) group(s); or    -   (iii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (iv) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y— A′-Y—R¹, wherein A₁ is as defined above,        A′ is aryl or heteroaryl, and each of A₁ and A′ is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); or    -   (v) —Z—Y-A¹ and R² is hydrogen, a polar group (PL), or a        non-polar group (NPL), wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vi) —Z—Y-A′, and R² is —X-A″, wherein A′ and A″ are,        independently, aryl or heteroaryl, and each of A′ and A″ is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vii) R¹ and R² are, independently, a polar group (PL) or a        non-polar group (NPL); or    -   (viii) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino, or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from the groupconsisting of hydrogen, alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 500;

and an ophthalmically or otically acceptable excipient.

US Application Publ. No. US 2006-0041023 A1 discloses antimicrobialpolymers and oligomers of Formula IV that can be used in thecompositions of the present invention.

For example, oligomers that are preferred for use in the ophthalmic orotic compositions of the present invention are those oligomers ofFormula IV wherein m is 1 to about 25, 1 to about 20, 1 to about 10, 1to about 5, or 1, 2, or 3.

Thus, preferred ophthalmic or otic compositions also comprise anoligomer of Formula IV having Formula IVa, Formula IVb, or Formula IVc:

R¹—X-A₁-X—Z—Y-A₂-Y—R²  (IVa)

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—R²  (IVb)

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—Z—Y-A₂-Y—R²  (IVc)

or an acceptable salt or solvate thereof,wherein:

X is NR⁸, —NR⁸NR⁸—, C═O, or O; Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O; and R⁸is hydrogen or alkyl;

Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is hydrogen, a polar group (PL), or a non-polar group (NPL), and R²is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³⁵—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2;

and an ophthalmically or otically acceptable excipient.

US Application Publ. No. US 2006-0041023 A1 discloses antimicrobialpolymers and oligomers of Formulae IVa, IVb, and IVc that can be used inthe compositions of the present invention.

Preferred ophthalmic or otic compositions comprise oligomers of FormulaeIVa, IVb and IVc wherein X and Y are, independently, NR⁸, C═O, or O; Zis C═O or —NR⁸NR⁸; and R⁸ is hydrogen or C₁-C₆ alkyl. Especiallypreferred for use in the ophthalmic or otic compositions are thoseoligomers wherein X and Y are each NR⁸, Z is C═O, and R⁸ is hydrogen.Also preferred are oligomers wherein X and Y are each C═O, and Z is—N(R⁸)N(R⁸)—, especially wherein R⁸ is hydrogen.

Also preferred for use in the ophthalmic or otic compositions are thoseoligomers of Formulae IVa, IVb and IVc wherein A₁ and A₂ areindependently optionally substituted o-, m-, or p-phenylene. Thoseoligomers wherein A₁ and A₂ are optionally substituted m-phenylene areespecially preferred. Also preferred are polymers and oligomers ofFormula IV wherein one of A₁ and A₂ is o-, m-, or p-phenylene, and theother of A₁ and A₂ is heteroarylene. Preferred heteroarylene groupsinclude, but are not limited to, pyridinylene, pyrimidinylene, andpyrazinylene.

Also preferred are oligomers of Formulae IVa, IVb and IVc wherein A₁ andA₂ are, independently, optionally substituted arylene or optionallysubstituted heteroarylene, and (i) each of A₁ and A₂ is substituted withone or two polar (PL) group(s) and one or two nonpolar (NPL) group(s);or (ii) one of A₁ and A₂ is substituted with one or two polar (PL)group(s) and the other of A₁ and A₂ is substituted with one or twononpolar (NPL) group(s).

Preferred ophthalmic or otic compositions also comprise oligomers ofFormulae IVa, IVb and IVc are those wherein R¹ is hydrogen or a polargroup (PL). Especially preferred oligomers are those wherein R¹ is—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, wherein R⁵,R^(5′), R^(5″), V, U^(PL), and pPL are as defined above, and q1PL andq2PL are each 0, so that especially preferred oligomers of Formulae IVa,IVb and IVc are those wherein R¹ is —U^(PL)—(CH₂)_(pPL)—V. Preferred R¹polar groups are those wherein U^(PL) is absent or is O, S, NH,—C(═O)O—, or —C(═O); pPL is 0 to 6, especially 1 to 4; and V is amino,aminoalkyl, amidino, guanidino, aryl, or heteroaryl optionallysubstituted with one or more amino, guanidino, amidino, or halo groups.

Preferred values for each of R³, R^(3′), and R^(3″) are hydrogen, C₁-C₆alkyl, and C₁-C₆ alkoxy. Hydrogen is an especially preferred value forR³, R^(3′), and R^(3″).

Preferred values of R^(4′) are hydrogen, C₁-C₁₀ alkyl, C₃-C₁₈ branchedalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, and C₆-C₁₀ aryl, especiallyphenyl. Especially preferred values of R^(4′) are C₁-C₁₀ alkyl andC₃-C₁₈ branched alkyl. Suitable C₁-C₁₀ alkyl and C₃-C₁₈ branched alkylgroups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, andn-pentyl.

Preferred values of U^(NPL) are O, S, NH, —C(═O)—, —C(═O)O—, —R³S— and—R³O—. Preferred oligomers of Formulae IVa, IVb and IVc are also thosewherein U^(NPL) is absent.

Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 areespecially preferred, with values of pNPL of 0, 1, or 2 most preferred.

Preferred values of q1NPL and q2NPL are 0 or 1. Values of q1NPL andq2NPL of 0 or 1 are especially preferred, with a value of 0 being themost preferred for each of q1NPL and q2NPL.

In preferred ophthalmic or otic compositions, in the oligomers ofFormulae IVa, IVb and IVc, the —(CH²)_(pNPL)— alkylene chain in NPL isunsubstituted or substituted with one or more alkyl groups. Morepreferred are those oligomers wherein the —(CH₂)_(pNPL)— alkylene chainin NPL is unsubstituted.

An especially preferred value of NPL for polymers and oligomers ofFormulae IVa, IVb and IVc is C₁-C₆ alkyl. Examples of preferred valuesfor NPL are n-propyl, isopropyl, n-butyl, and tert-butyl.

Preferred oligomers of Formulae IVa, IVb and IVc for use in theophthalmic or otic compositions are also those wherein PL is—(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5″))_(q2PL)—V, and R⁵, R^(5′),R^(5″), V, U^(PL), pPL, q1PL, and q2PL are as defined above.

Preferred values for R⁵, R^(5′), and R^(5″) are hydrogen, C₁-C₆ alkyl,and C₁-C₆ alkoxy. Hydrogen is an especially preferred value for each ofR⁵, R^(5′), and R^(5″).

Preferred values of U^(PL) are O, S, NH, —C(═O)—, —C(═O)O—, —R⁵S—, and—R⁵⁰—, wherein R⁵ is hydrogen or C₁-C₆ alkyl. Especially preferredvalues of U^(PL) are O, S, and —C(═O).

Preferred values of V are nitro, cyano, amino, hydroxy, C₁-C₆ alkoxy,C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino,guanyl, semicarbazone, C₆-C₁₀ aryl, heterocycle, and heteroaryl,preferably any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy,lower acylamino, or benzyloxycarbonyl.

Suitable heteroaryl groups include indolyl, 3H-indolyl, 1H-isoindolyl,indazolyl, benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitableheterocycle groups include piperidinyl, piperazinyl, imidazolidinyl,pyrrolidinyl, pyrazolidinyl, and morpholinyl.

Especially preferred values of V are amino, C₁-C₆ alkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, diazamino, amidino,and guanidino, preferably any of which is optionally substituted withone or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanyl, guanidino, oraminoalkoxy. Values of V that are most preferred are amino andguanidino.

Preferred values of pPL are 0 to 6; values of pPL of 0 to 4 areespecially preferred, with values of pPL of 2 to 4 especially preferred.

Preferred values of q1PL and q2PL are 0 or 1. Values of q1PL and q2PL of0 or 1 are especially preferred, with a value of 0 being especiallypreferred for each of g1 PL and q2PL.

In the preferred ophthalmic or otic compositions of the invention, inthe oligomers of Formulae IVa, IVb, and IVc, the —(CH₂)_(pPL)— alkylenechain in PL is optionally substituted with one or more amino or hydroxygroups.

Examples of oligomers of Formulae I, II, IIa, IV, IVa, IVb, and IVc thatcan be used in the ophthalmic or otic compositions of the presentinvention include, but are not limited to, the individual oligomersdisclosed in US Application Publ. No. 2006-0041023 A1 and U.S. Pat. No.7,173,102.

In some aspects, the ophthalmic or otic compositions of the presentinvention comprise a polymer or oligomer of Formula V:

R¹—[-A₁-W-A₂-W-]_(m)—R²  (V)

or an acceptable salt or solvate thereof,wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

-   -   (i) A₁ and A₂ are independently optionally substituted with one        or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (ii) one of A₁ or A₂ is as defined above and is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); and the        other of A₁ or A₂ is the group —C≡C(CH₂)_(p)C≡C—, wherein p is 0        to 8, and the

—(CH₂)_(p)— alkylene chain is optionally substituted with one or moreamino or hydroxyl groups;

W is absent, or represents —CH₂—, —CH₂—CH₂—, —CH═CH—, or —C≡C—;

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-W-A₂-R¹, wherein each of A₁ and A₂ is as defined        above and is optionally substituted with one or more polar (PL)        group(s), one or more non-polar (NPL) group(s), or a combination        of one or more polar (PL) group(s) and one or more non-polar        (NPL) group(s); or    -   (iii) A′-W— and R² is -A₁-W-A′, wherein A′ is aryl or        heteroaryl, either of which is optionally substituted with one        or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (iv) A′-W— and R² is -A′, wherein A′ is aryl or heteroaryl,        either of which is optionally substituted with one or more polar        (PL) group(s), one or more non-polar (NPL) groups(s), or a        combination of one or more polar (PL) group(s) and one or more        non-polar (NPL) group(s); or    -   (v) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(con)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio,lower acylamino, or benzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0 to 2; and

m is 1 to at least about 500;

with the proviso that if A₁ and A₂ are thiophene, the polar groupscannot be 3-(propionic acid) or methoxy(diethoxy)ethyl and the nonpolargroup cannot be n-dodecyl; and an ophthalmically or otically acceptableexcipient.

US Appl. Publ. No. US 2005-0287108 A1 discloses antimicrobial polymersand oligomers of Formula V that can be used in the compositions of thepresent invention.

For example, oligomers that are preferred for use in the ophthalmic orotic compositions of the present invention are those oligomers ofFormula V wherein m is 1 to about 25, 1 to about 20, 1 to about 10, 1 toabout 7, 1 to about 5, or 1, 2, or 3.

Thus, preferred ophthalmic or otic compositions of the invention alsocomprise oligomers of Formula Va:

R¹-A₁-W-A₂-W-A₁-R²  (Va)

or an acceptable salt or solvate thereof,wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

-   -   (i) A₁ and A₂ are independently optionally substituted with one        or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (ii) one of A₁ or A₂ is as defined above and is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); and the        other of A₁ or A₂ is the group —C≡C(CH₂)_(p)C≡C—, wherein p is 0        to 8, and the —(CH₂)_(p)— alkylene chain is optionally        substituted with one or more amino or hydroxyl groups;

W is —C≡C—;

R¹ is hydrogen, a polar group (PL), a non-polar group (NPL), or —W-A′,

wherein A′ is aryl or heteroaryl, either of which is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, whereinR³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³—O—, —R³—S—, —S—C═N— and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the alkylene chain —(CH²)_(pNPL)— is optionally substituted with one ormore alkyl, amino, or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)—(NR^(5′)) _(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio,lower acylamino, or benzyloxycarbonyl;

the alkylene chain —(CH₂)_(pPL)— is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0 to 2;

and an ophthalmically or otically acceptable excipient.

Preferred oligomers of Formula Va for use in the ophthalmic or oticcompositions are those oligomers of Formula Va wherein A₁ and A₂ are,independently, optionally substituted o-, m-, or p-phenylene, withm-phenylene being especially preferred. Also preferred are oligomers ofFormula Va wherein one of A₁ or A₂ is o-, m-, or p-phenylene, and theother of A₁ or A₂ is heteroarylene. Preferred heteroarylene groupsinclude, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl.

Preferred oligomers of Formula Va are also those wherein A₁ issubstituted with one or two polar (PL) group(s) and A₂ is unsubstituted.Especially preferred are those oligomers wherein A₁ is substituted withone polar (PL) group and A₂ is unsubstituted.

Preferred ophthalmic or otic compositions also comprise oligomers ofFormula Va wherein R¹ is hydrogen, a polar group (PL), or a non-polargroup (NPL); and R² is R¹. More preferred are oligomers of Formula Vawherein R¹ is selected from hydrogen, halo, nitro, cyano, C₁-C₆ alkoxy,C₁-C₆ alkoxycarbonyl, and benzyloxycarbonyl. Oligomers of Formula Vawherein R¹ and R² are halo are especially preferred.

Preferred R³, R^(3′), and R^(3″) groups include hydrogen and C₁-C₄alkyl. Especially preferred are those oligomers of Formula Va whereinR³, R^(3′), and R^(3″) are each hydrogen.

Preferred R⁴ groups include hydrogen, C₁-C₁₀ alkyl, C₃-C₁₈ branchedalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, or C₆-C₁₀ aryl, especiallyphenyl. Oligomers wherein R⁴ is hydrogen, C₁-C₁₀ alkyl, and C₃-C₁₈branched alkyl, any of which is optionally substituted with one or moreC₁-C₄ alkyl or halo groups, are especially preferred.

Preferred oligomers of Formula Va are also those wherein U^(NPL) is O,S, NH, —(C═O)—, —C(═O)O—, —R³O—, or —R³S—. Oligomers of Formula Vawherein U^(NPL) is O, S, or —(C═O)— are especially preferred. Oligomersof Formula Va wherein U^(NPL) is absent are also preferred.

Preferred oligomers of Formula Va also include those oligomers whereinthe alkylene chain —(CH²)_(pNPL)— is optionally substituted with one ormore alkyl groups. Especially preferred are those oligomers in which thealkylene chain is unsubstituted. Also preferred are those oligomers ofFormula Va wherein pNPL is 0 to 8, or 1 to 6, or, more preferably, 2 to4.

Preferred oligomers of Formula Va are those wherein q1NPL and q2NPL areindependently 0 or 1.

In some embodiments, preferred ophthalmic or otic compositions compriseoligomers wherein NPL is n-pentoxy, n-butoxy, sec-butoxy, tert-butoxy,propyloxy, ethyloxy, methoxy, or phenoxy.

Preferred ophthalmic or otic compositions also comprise oligomers ofFormula Va wherein one or more PL are halo, especially bromo or iodo.

Preferred oligomers of Formula Va for use in the ophthalmic or oticcompositions include those wherein PL is—(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5″))_(q2PL)—V, and R⁵, R^(5′),R^(5″), V, U^(PL), and pPL, and q1PL and q2PL are as defined above.

Preferred values for R⁵, R^(5′), and R^(5″) are hydrogen, C₁-C₆ alkyl,and C₁-C₆ alkoxy. Hydrogen is an especially preferred value for each ofR⁵, R^(5′), and R^(5″).

Preferred values of U^(PL) are O, S, NH, —(C═O)—, —C(═O)O—, —R⁵⁰—, and—R⁵S—. Also preferred are oligomers of Formula Va wherein U^(PL) isabsent.

Preferred oligomers of Formula Va also are those wherein q1PL and q2PLare, independently, 0 or 1.

Preferred ophthalmic or otic compositions also comprise oligomers ofFormula Va wherein V is nitro, cyano, amino, hydroxyl, C₁-C₆ alkoxy,C₁-C₆ alkylthio, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, —NH(CH₂)_(p)NH₂,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,heterocycle, or heteroaryl, any of which is optionally substituted withone or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂,—N(CH₂CH₂NH₂)₂, amidino, guanyl, guanidine, or aminoalkoxy. Suitableheteroaryl groups include indolyl, 3H-indolyl, 1H-isoindolyl, indazolyl,benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitable heterocycle groupsinclude piperidinyl, piperazinyl, imidazolidinyl, pyrrolidinyl,pyrazolidinyl, and morpholinyl.

Especially preferred values of V include amino, C₁-C₆ alkylamino, C₁-C₆dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino, amidino,guanidino, and guanyl, any of which is optionally substituted with oneor more of amino, halo, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, amidino,guanyl, guanidine, or aminoalkoxy.

Especially preferred oligomers of Formula Va for use in the preferredophthalmic compositions are those wherein PL is halo, guanidinomethyl,guanidinoethyl, guanidinopropyl, aminomethyl, aminoethyl, aminopropyl,aminoethylaminocarbonyl, or aminomethylaminocarbonyl.

Preferred oligomers of Formula Va are also those wherein pPL is 0 to 4.Especially preferred are those oligomers wherein pPL is 0 to 2.

Thus, in some embodiments, especially preferred ophthalmic or oticcompositions of the present invention comprise an oligomer of Formula Vawherein:

A₁ and A₂ are, independently, optionally substituted m-phenylene,wherein A₁₁s optionally substituted with two polar (PL) groups, and A₂is unsubstituted;

R¹ is a polar group;

PL is —(NR^(5′))_(q1PL)—U^(PL)—(CH²)_(pPL)—(NR^(5′))_(q2PL)—V, wherein:

U^(PL) is absent or selected from O, S, NR⁵, and —C(═O)—;

V is selected from amino, amidino, and guanidino, any of which isoptionally substituted with one or more of amino, halo, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkylhio, and lower acylamino;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0;

and an ophthalmically acceptable excipient.

Especially preferred are oligomers of Formula Va wherein R¹ is halo, andPL is —U^(PL)—(CH₂)_(pPL)—V, wherein U^(PL) is absent; V is selectedfrom amino, amidino, and guanidino, any of which is optionallysubstituted with one or more of amino or halo; and pPL is 0 to 6.

Exemplary structures of oligomers of Formula Va within the scope of theinvention include the following, as well as those individual oligomersdisclosed in U.S. Application Publication No. 2005-0287108, the contentsof which is fully incorporated herein by reference.

and ophthalmically or otically acceptable salts thereof.

In some aspects, the ophthalmic or otic compositions of the presentinvention comprise a random copolymer of Formula VI:

A-(B)_(n1)-(D)_(m1)-H  (VI)

or an acceptable salt or solvate thereof,wherein:

A is the residue of a chain transfer agent;

B is —[CH₂—C(R¹¹)(B₁₁)]— wherein B₁₁ is —X₁₁—Y₁₁—Z₁₁, wherein

X₁₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₁₁ is absent;

Y₁₁ is O, NH, or optionally substituted C₁₋₆ alkylene; or Y₁₁ is absent;

Z₁₁ is —Z_(11A)-Z_(11B), wherein Z_(11A) is alkylene, arylene, orheteroarylene, any of which is optionally substituted; or Z_(11A) isabsent; and Z₁₁₃ is -guanidino, -amidino, —N(R³)(R⁴), or—N⁺(R³)(R⁴)(R⁵), wherein R³, R⁴, and R⁵ are, independently, hydrogen,alkyl, aminoalkyl, aryl, heteroaryl, heterocyclic, or aralkyl; or

Zn is pyridinium

or phosphonium

wherein

R⁸¹, R⁹¹¹, R⁹²¹, and R⁹³¹ are independently, hydrogen or alkyl;

R¹¹ is hydrogen or C₁₋₄ alkyl;

D is —[CH₂—C(R²¹)(D₂₁)]—, wherein D₂₁ is —X₂₁—Y₂₁—Z₂₁, wherein

X₂₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₂₁ is absent;

Y₂₁ is O, NH, or optionally substituted C₁₋₆ alkylene, or Y₂₁ is absent;

Z₂₁ is alkyl, cycloalkyl, alkoxy, aryl, or aralkyl, any of which isoptionally substituted;

R²¹ is hydrogen or C₁₋₄ alkyl;

m₁, the mole fraction of D monomer, is about 0.1 to about 0.9; and

n₁, the mole fraction of B monomer, is 1-m₁;

wherein the copolymer is a random copolymer of B and D monomers, and

wherein the copolymer has a degree of polymerization of about 5 to about50;

and an ophthalmically or otically acceptable excipient.

US Application Publ. No. US 2006/0024264 A1 discloses randomantimicrobial copolymers of Formula VI that can be used in thecompositions of the present invention. Preferred ophthalmic or oticcompositions comprise a random copolymer of Formula VI wherein:

A is C₁₋₄ alkoxycarbonyl(C₁₋₄alkylthio;

X₁₁ and X₂₁ are carbonyl;

Y₁₁ and Y₂₁ are O;

Z₁₁ is —Z_(11A)-Z_(11B), wherein Z_(11A) is C₁₋₆ alkylene optionallysubstituted with C₁₋₄ alkyl or aryl; and Z_(11B) is —N(R³¹)(R⁴¹) or—N⁺(R³¹)(R⁴¹)(R⁵¹), wherein R³¹, R⁴¹, and R⁵¹ are, independently,hydrogen C₁₋₄ alkyl;

Z₂₁ is C₁₋₆ alkyl, C₁₋₆ aryl, or C₁₋₆ ar(C₁₋₄)alkyl;

R^(1l) and R²¹ are independently hydrogen or methyl;

m₁ is about 0.35 to about 0.60; and

wherein the copolymer has a degree of polymerization of about 5 to about10; and an ophthalmically or otically acceptable excipient.

When any variable occurs more than one time in any constituent or in anyof the polymers or oligomers recited for any of the general Formulaeabove (for example, in Formula I, Formula II, Formula IIa, Formula IV,Formula IVa, Formula IVb, Formula IVc, Formula V, Formula Va, or FormulaVI), its definition on each occurrence is independent of its definitionat every other occurrence. Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

It is understood that the present invention encompasses the use ofstereoisomers, diastereomers and optical isomers of the polymers andoligomers disclosed herein, as well as mixtures thereof, for use in theophthalmic or otic compositions and methods of the present invention.Additionally, it is understood that stereoisomers, diastereomers andoptical isomers of the disclosed polymers and oligomers, and mixturesthereof, are within the scope of the present invention. By way ofnon-limiting example, the mixture can be a racemate or the mixture maycomprise unequal proportions of one particular stereoisomer over theother. Thus, in some aspects of the invention, the disclosed polymersand oligomers are provided as mixtures that are racemates. Additionally,the polymers and oligomers can be provided as a substantially purestereoisomers, diastereomers and optical isomers. Thus, in some aspectsof the invention, the polymers and oligomers in the compositions of theinvention are provided as substantially pure stereoisomers,diastereomers, or optical isomers.

In other aspects of the present invention, the polymers and oligomers inthe ophthalmic or otic compositions are provided in the form of anacceptable salt (for example, a pharmaceutically acceptable salt) fortreating microbial infections. Polymer or oligomer salts can be providedfor pharmaceutical use, or as an intermediate in preparing thepharmaceutically desired form of the polymer or oligomer. One polymer oroligomer salt that is considered to be acceptable is the hydrochlorideacid addition salt. Since one or more of the disclosed polymers andoligomers may be polyionic, such as a polyamine, the acceptable polymeror oligomer salt can be provided in the form of a poly(aminehydrochloride). Examples of other acceptable salts include, but are notlimited to, those having sodium, potassium, or ammonium cations, and/orthose having chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate, bisulfite, mesylate, esylate,napsydisylate, tosylate, besylate, orthophoshate, acetate, gluconate,glutamate, lactate, malonate, fumarate, tartrate, maleate, ortrifluoroacetate anions. In some embodiments, acceptable salts are thosehaving mesylate, chloride, sulfate, esylate, napsydisylate, tosylate,besylate, phosphate, orthophoshate, acetate, gluconate, glutamate,lactate, malonate, citrate, fumarate, tartrate, maleate, ortrifluoroacetate anions. In other embodiments, acceptable salts includesodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite, and ammonium sulfate.

In some aspects of the invention, the disclosed polymers and oligomers(such as the polymers and/or oligomers of Formulae I, II, IIa, IV, IVa,IVb, IVc, V, Va, and VI) are derivatives referred to as prodrugs. Theexpression “prodrug” denotes a derivative of a known direct acting drug,which derivative has enhanced delivery characteristics and therapeuticvalue as compared to the drug, and is transformed into the active drugby an enzymatic or chemical process.

Unless otherwise defined, the terms below have the following meanings.

The term “alkyl” as used herein by itself or as part of another grouprefers to both straight and branched chain radicals from 1 to 12carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

The term “alkenyl” as used herein refers to a straight or branched chainradical of 2 to 20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

The term “alkynyl” as used herein refers to a straight or branched chainradical of 2 to 20 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, acetylene,1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

The term “alkylene” as used herein refers to an alkyl linking group, forexample, an alkyl group that links one group to another group in amolecule.

The term “alkoxy” as used herein refers to mean a straight or branchedchain radical of 1 to 20 carbon atoms, unless the chain length islimited thereto, bonded to an oxygen atom, including, but not limitedto, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8carbon atoms in length, and even more preferred 1 to 6 carbon atoms inlength.

The term “aryl” as used herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6 to 10 carbons in the ringportion, such as the carbocyclic groups phenyl, naphthyl ortetrahydronaphthyl. The term “aryl” can represent carbocyclic arylgroups, such as phenyl, naphthyl or tetrahydronaphthyl, as well asheterocyclic aryl (“heteroaryl”) groups, such as pyridyl, pyrimidinyl,pyridazinyl, furyl, and pyranyl.

The term “arylene” as used herein by itself or as part of another grouprefers to an aryl linking group, for example, an aryl group that linksone group to another group in a molecule.

The term “cycloalkyl” as used herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms, morepreferably, 3 to 8 carbon atoms. Typical examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andcyclononyl.

The term “halogen” or “halo” as used herein by itself or as part ofanother group refers to chlorine, bromine, fluorine, or iodine.

The term “hydroxy” or “hydroxyl” as used herein by itself or as part ofanother group refers to an —OH group.

The term “heteroaryl” as used herein refers to groups having 5 to 14ring atoms; 6, 10, or 14 π-electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2, or 3 oxygen, nitrogen or sulfurheteroatoms. Examples of heteroaryl groups include, but are not limitedto, thienyl, imadizolyl, oxadiazolyl, isoxazolyl, triazolyl, pyridyl,pyrimidinyl, pyridazinyl, furyl, pyranyl, thianthrenyl, pyrazolyl,pyrazinyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl,xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, indolyl, indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl,furazanyl, and phenoxazinyl groups. Especially preferred heteroarylgroups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole,imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine,and 2-aminopyridine.

The term “heteroarylene” as used herein by itself or as part of anothergroup refers to a heteroaryl linking group, such as, a heteroaryl groupthat links one group to another group in a molecule.

The term “heterocycle” or “heterocyclic ring”, as used herein exceptwhere noted, represents a stable 5- to 7-membered mono- or bicyclic orstable 7- to 10-membered bicyclic heterocyclic ring system any ring ofwhich may be saturated or unsaturated, and which consists of carbonatoms and from one to three heteroatoms selected from N, O, and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. Especially useful are rings containing oneoxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfurcombined with one or two nitrogen atoms. The heterocyclic ring may beattached at any heteroatom or carbon atom which results in the creationof a stable structure. Examples of such heterocyclic groups include, butare not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, andoxadiazolyl. Morpholino is the same as morpholinyl.

The term “alkylamino” as used herein by itself or as part of anothergroup refers to an amino group which is substituted with one alkyl grouphaving from 1 to 6 carbon atoms. The term “dialkylamino” as used hereinby itself or as part of an other group refers to an amino group which issubstituted with two alkyl groups, each having from 1 to 6 carbon atoms.

The term “alkylthio” as used herein by itself or as part of an othergroup refers to a thio group which is substituted with one alkyl grouphaving from 1 to 6 carbon atoms.

The term “lower acylamino” as used herein by itself or as part of another group refers to an amino group substituted with a C₁-C₆alkylcarbonyl group.

The term “chemically nonequivalent termini” as used herein refers to afunctional group such as an ester, amide, sulfonamide, or N-hydroxyoximethat, when reversing the orientation of the functional group (forexample, —(C═O)O—) produces different chemical entities (for example,—R¹C(═O)OR²— versus —R¹OC(═O)R²—).

The polymers and oligomers employed in the ophthalmic compositions ofthe present invention (e.g., the polymers and/or oligomers of FormulaeI, II, IIa, IV, IVa, IVb, IVc, V, Va, and VI) can be prepared asdescribed in the following patents and patent publications: US PublishedPatent Appl. Nos. US 2006-0041023 A1, US 2004-0202639 A1, US2005-0287108 A1, and US 2006-0024264 A1, as well as U.S. Pat. No.7,173,102. For example, US Pat. Appl. Publ. No. US 2006-0041023 A1discloses methods for the design, synthesis, and testing of polymers andoligomers of Formulae I, II, IIa, IV, IVa, IVb, and IVc. US Pat. Appl.Publ. No. US 2005/0287108 A1 discloses methods for the design,synthesis, and testing of polymers and oligomers of Formula V andFormula Va.

Examples of the design, synthesis, and testing of arylamide oligomers, asubgroup of oligomers of Formula II and Formula IIa, are also presentedin Tew et al., Proc. Natl. Acad. Sci. USA, 2002, 99, 5110-5114 and inWIPO Publication No. WO 2004/082634.

The oligomers can be synthesized by solid-phase synthetic procedureswell know to those of skill in the art. See, for example, Tew et al.,Proc. Natl. Acad. Sci. USA, 2002, 99, 5110-5114; Barany et al., Int. J.Pept. Prot. Res., 1987, 30, 705-739; Solid-phase Synthesis: A PracticalGuide, Kates, S. A., and Albericio, F., eds., Marcel Dekker, New York(2000); and Dorwald, F. Z., Organic Synthesis on Solid Phase: Supports,Linkers, Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002).

The ophthalmic or otic compositions can be tested for anti-microbialactivity by methods known to those of skill in the art. For example,anti-microbial assays suitable for testing the antimicrobial activity ofthe ophthalmic or otic compositions of the invention are described, forexample, US Pat. Appl. Publ. No. US 2006-0041023 A1; Tew et al., Proc.Natl. Acad. Sci. USA, 2002, 99, 5110-5114; and Liu et al., J. Amer.Chem. Soc., 2001, 123, 7553-7559.

Compositions

The ophthalmic and otic compositions of the present invention can takethe form of a liquid or solid, including, e.g., but not limited to, asolution, a suspension, an emulsion, a gel, an ointment, or a solidarticle that can be inserted in a suitable location in the eye.

In some embodiments, a composition of the present invention is in theform of a liquid wherein the active agent (i.e., one of the faciallyamphiphilic polymers or oligomers disclosed herein) is present insolution, in suspension, as an emulsion, or as a “solution/suspension.”The term “solution/suspension” as used herein refers to a liquidcomposition wherein a first portion of the active agent is present insolution and a second portion of the active agent is present inparticulate form, in suspension in a liquid matrix. In some embodiments,the liquid composition is in the form of a gel. In other embodiments,the liquid composition is aqueous. In other embodiments, the compositionis in the form of an ointment.

In yet other embodiments, the composition is in the form of a solidarticle. For example, in some embodiments, the ophthalmic composition isa solid article that can be inserted in a suitable location in the eye,such as between the eye and eyelid or in the conjunctival sac, where itreleases the active agent as described, for example, U.S. Pat. No.3,863,633; U.S. Pat. No. 3,867,519; U.S. Pat. No. 3,868,445; U.S. Pat.No. 3,960,150; U.S. Pat. No. 3,963,025; U.S. Pat. No. 4,186,184; U.S.Pat. No. 4,303,637; U.S. Pat. No. 5,443,505; and U.S. Pat. No.5,869,079. Release from such an article is usually to the cornea, eithervia the lacrimal fluid that bathes the surface of the cornea, ordirectly to the cornea itself, with which the solid article is generallyin intimate contact. Solid articles suitable for implantation in the eyein such fashion are generally composed primarily of polymers and can bebioerodible or non-bioerodible. Bioerodible polymers that can be used inthe preparation of ocular implants carrying one or more of theanti-microbial, facially amphiphilic polymer or oligomer active agentsin accordance with the present invention include, but are not limitedto, aliphatic polyesters such as polymers and copolymers ofpoly(glycolide), poly(lactide), poly(epsilon-caprolactone),poly-(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids,polyorthoesters, polyanhydrides, aliphatic polycarbonates and polyetherlactones. Suitable non-bioerodible polymers include silicone elastomers.

The present invention provides anti-microbial ophthalmic or oticcompositions comprising a polymer of an oligomer of Formula I, FormulaII, Formula IIa, Formula IV, Formula IVa, Formula IVb, Formula IVc,Formula V, Formula Va, or Formula VI and an ophthalmically or oticallyacceptable excipient.

The polymer or oligomer is typically present in the ophthalmic or oticcomposition in an “effective amount” or “effective concentration.” Theterms “effective amount,” “effective concentration,” or “amounteffective,” as used herein in reference to a polymer or oligomer in acomposition of the present invention, refers to the amount of thepolymer or oligomer sufficient to treat or prevent an ophthalmicinfection in an eye of an animal, or to treat or prevent an oticinfection in an ear of an animal.

The “effective amount” or concentration of the polymer or oligomer inthe composition will vary and depends, among other factors, on theparticular facially amphiphilic polymer or oligomer (active agent) beingadministered (e.g., on the relative antimicrobial activity of thespecific polymer or oligomer); the mode of administration; the residencetime provided by the particular formulation of the polymer or oligomer;the species, age and body weight of the subject; the intended use of thecomposition (e.g., treatment of existing infections or prevention ofpost-surgical infections); the particular condition for which treatmentor prophylaxis is sought; and the severity of the condition.

The activity of antimicrobials is generally expressed as the minimumconcentration of a compound (active agent) required to inhibit thegrowth of a specified pathogen. This concentration is also referred toas the “minimum inhibitory concentration” or “MIC.” The term “MIC₉₀”refers to the minimum concentration of an antimicrobial active agentrequired to inhibit the growth of ninety percent (90%) of the testedisolates for one particular organism. The concentration of a compoundrequired to totally kill a specified bacterial species is referred to asthe “minimum bactericidal concentration” or “MCB.”

The “effective amount” or concentration of the polymer or oligomer inthe compositions of the invention will generally be an amount sufficientto provide a concentration on or in the affected eye or ear tissue equalto or greater than the MIC₉₀ level for the selected polymer or oligomer,relative to the microbes commonly associated with the infection. Thus,the “effective amount” or concentration of the polymer or oligomer inthe ophthalmic or otic composition will generally be the amount of thepolymer or oligomer sufficient to provide a concentration on or in theeye or ear tissue(s) equal to or greater than the MIC₉₀ level for thepolymer or oligomer, relative to microbes commonly associated with theophthalmic or otic infection.

Thus, for example, in the ophthalmic and otic compositions of thepresent invention, an effective concentration of the antimicrobialpolymer or oligomer in the composition will generally be from about0.01% to about 20% by weight (i.e., wt %) of the composition. Moretypically, it will be about 0.05% to about 10% by weight, about 0.1% toabout 8.0% by weight, about 0.5% to about 5.0% by weight, about 1.0% toabout 5.0% by weight, or about 2.0% to about 4.0% of the composition.For example, in ophthalmic compositions in the form of solidsuspensions, such as ointments, an effective concentration of theantimicrobial polymer or oligomer will generally be from about 1% toabout 5% by weight (wt %) of the composition.

The ophthalmic and otic compositions of the invention are preferablysterile and have physical properties (e.g., osmolality and pH) that arespecially suited for application to ophthalmic or otic tissues,including tissues that have been compromised as the result ofpreexisting disease, trauma, surgery or other physical conditions. Forexample, aqueous compositions of the invention typically have a pH inthe range of 4.5 to 8.0, more preferably, 6.0 to 8.0, or 6.5 to 8.0, or7.0 to 8.0.

In addition to one or more of the polymers or oligomers disclosedherein, the ophthalmic or otic compositions of the invention can alsocomprise one or more ophthalmically or otically acceptable excipients.

The term “ophthalmically acceptable” as used herein means having nopersistent detrimental effect on the treated eye or the functioningthereof, or on the general health of the subject being treated. However,it will be recognized that transient effects such as minor irritation ora “stinging” sensation are common with topical ophthalmic administrationof drugs and the existence of such transient effects is not inconsistentwith the composition, formulation, or ingredient (e.g., excipient) inquestion being “ophthalmically acceptable” as herein defined. However,preferred ophthalmically acceptable compositions, formulations, andexcipients are those that cause no substantial detrimental effect, evenof a transient nature.

Similarly, the term “otically acceptable,” as used herein, means havingno persistent detrimental effect on the treated ear or the functioningthereof, or on the general health of the subject being treated.Preferred otically acceptable compositions, formulations, and excipientsare those that cause no substantial detrimental effect, even of atransient nature. Ophthalmically and otically acceptable excipientsinclude, but are not limited to, viscosity-enhancing agents,preservatives, stabilizers, antioxidants, suspending agents,solubilizing agents, buffering agents, lubricating agents,ophthalmically or otically acceptable salts, and combinations thereof.

For example, aqueous ophthalmic compositions of the present invention,when in suspension or solution form, are preferably viscous ormucoadhesive, or both viscous or mucoadhesive, and thus comprise aviscosity-enhancing agent. Examples of suitable viscosity-enhancingagents include, but are not limited to, glycerin, polyvinyl alcohol,polyvinyl pyrrolidone, methylcellulose, hydroxypropylmethylcellulose,hydroxyethyl-cellulose, carboxymethylcellulose, hydroxypropylcellulose,and/or various gelling agents. For example, in some embodiments, theviscosity-enhancing agent is selected from methylcellulose,hydroxypropyl-methylcellulose, polyvinyl alcohol, and glycerol. Suchagents are generally employed in the compositions of the invention at aconcentration of about 0.01% to about 3% by weight.

Thus, for ophthalmic compositions of the present invention, in someembodiments, the ophthalmically acceptable excipient is aviscosity-enhancing agent or a promoter of mucoadhesion, such ascarboxymethylcellulose. In such embodiments, the concentration ofcarboxymethylcellulose in the aqueous suspension or solution is 0.1% to5% by weight or about 0.1% to about 2.5% by weight. Thecarboxymethylcellulose is preferably in the form of sodiumcarboxymethylcellulose substituted to a degree that the sodium contentof the sodium carboxymethylcellulose is about 1% to about 20%.

In other embodiments, the ophthalmic composition is an in situ gellableaqueous composition, more preferably, an in situ gellable aqueoussolution. Such a composition comprises a gelling agent in aconcentration effective to promote gelling upon contact with the eye orwith lacrimal fluid in the exterior of the eye, enabling the compositionto remain in the eye for a prolonged period without loss by lacrimaldrainage. Suitable gelling agents non-restrictively includethermosetting polymers such as tetra-substituted ethylene diamine blockcopolymers of ethylene oxide and propylene oxide (e.g., poloxamine1307); polycarbophil; and polysaccharides such as gellan, carrageenan(e.g., kappa-carrageenan and iota-carrageenan), chitosan and alginategums.

The phrase “in situ gellable” as used herein is to be understood asembracing not only liquids of low viscosity that form gels upon contactwith the eye or with lacrimal fluid in the exterior of the eye, but alsomore viscous liquids such as semi-fluid and thixotropic gels thatexhibit substantially increased viscosity or gel stiffness uponadministration to the eye.

For example, in some embodiments of the present invention, theophthalmic composition is an in situ gellable aqueous solution,suspension or solution/suspension, comprising about 0.1% to about 6.5%,preferably about 0.5% to about 4.5%, by weight, based on the totalweight of the composition, of one or more lightly cross-linkedcarboxyl-containing polymers as gelling agents. A preferred gellingagent in this embodiment is polycarbophil. In other embodiments, thecomposition is an in situ gellable aqueous solution, suspension orsolution/suspension, preferably a solution, comprising about 0.1% toabout 2% by weight of a polysaccharide that gels when it contacts anaqueous medium having the ionic strength of lacrimal fluid. A preferredpolysaccharide is gellan gum, more preferably a low acetyl clarifiedgrade of gellan gum such as that sold under the trademark Gelrite®.Suitable partially deacylated gellan gums are disclosed in U.S. Pat. No.5,190,927.

In yet other embodiments, the composition is an in situ gellable aqueoussolution, suspension or solution/suspension, comprising about 0.2% toabout 3%, preferably about 0.5% to about 1%, by weight of a gellingpolysaccharide, preferably selected from gellan gum, alginate gum andchitosan, and about 1% to about 50% of a water-soluble film-formingpolymer, preferably selected from alkylcelluloses (e.g.,methylcellulose, ethylcellulose), hydroxyalkylcelluloses (e.g.,hydroxyethylcellulose, hydroxypropyl methylcellulose), hyaluronic acidand salts thereof, chondroitin sulfate and salts thereof, polymers ofacrylamide, acrylic acid and polycyanoacrylates, polymers of methylmethacrylate and 2-hydroxyethyl methacrylate, polydextrose,cyclodextrins, polydextrin, maltodextrin, dextran, polydextrose,gelatin, collagen, natural gums (e.g., xanthan, locust bean, acacia,tragacanth and carrageenan gums and agar), polygalacturonic acidderivatives (e.g., pectin), polyvinyl alcohol, polyvinylpyrrolidone andpolyethylene glycol. The composition can optionally contain agel-promoting counterion such as calcium in latent form, for exampleencapsulated in gelatin.

In yet other embodiments, the composition is an in situ gellable aqueoussolution, suspension or solution/suspension comprising about 0.1% toabout 5% of a carrageenan gum, e.g., a carrageenan gum having no morethan 2 sulfate groups per repeating disaccharide unit, such as e.g.,kappa-carrageenan, having 18-25% ester sulfate by weight,iota-carrageenan, having 25-34% ester sulfate by weight, and mixturesthereof.

In still other embodiments, the composition comprises a bioerodiblepolymer substantially as disclosed in U.S. Pat. No. 3,914,402. In someembodiments, the composition comprises an ophthalmically acceptablemucoadhesive polymer, selected, for example, fromhydroxypropylmethylcellulose, carboxymethylcellulose, carbomer (acrylicacid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil,polyethylene oxide, acrylic acid/butyl acrylate copolymer, sodiumalginate, and dextran.

Ophthalmic compositions of the invention preferably incorporate means toinhibit microbial growth, for example through preparation and packagingunder sterile conditions and/or through inclusion of an antimicrobiallyeffective amount of an ophthalmically acceptable preservative.

Suitable preservatives include, but are not limited to,mercury-containing substances such as phenylmercuric salts (e.g.,phenylmercuric acetate, borate and nitrate) and thimerosal; stabilizedchlorine dioxide; quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride;imidazolidinyl urea; parabens such as methylparaben, ethylparaben,propylparaben and butylparaben, and salts thereof; phenoxyethanol;chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol;phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.

Several preservatives may precipitate in the presence of otherexcipients in the composition and/or in the presence of the polymers andoligomers in the ophthalmic compositions of the present invention. Forexample, benzalkonium chloride can precipitate in a composition usingiota-carrageenan as a gelling agent. Thus, in those embodiments of theinvention in which a preservative is present, the preservative is onethat does not precipitate but remains in solution in the composition.

Optionally one or more stabilizers can be included in the compositionsof the invention to enhance chemical stability where required. Suitablestabilizers include, but are not limited to, chelating agents orcomplexing agents, such as, for example, the calcium complexing agentethylene diamine tetraacetic acid (EDTA). For example, an appropriateamount of EDTA or a salt thereof, e.g., the disodium salt, can beincluded in the composition to complex excess calcium ions and preventgel formation during storage. EDTA or a salt thereof can suitably beincluded in an amount of about 0.01% to about 0.5%. In those embodimentscontaining a preservative other than EDTA, the EDTA or a salt thereof,more particularly disodium EDTA, can be present in an amount of about0.025% to about 0.1% by weight.

One or more antioxidants can also be included in the ophthalmiccompositions of the invention. Suitable antioxidants include ascorbicacid, sodium metabisulfite, polyquaternium-1, benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, or other agents know to those ofskill in the art. Such preservatives are typically employed at a levelof from about 0.001% to about 1.0% by weight.

In some embodiments of the present invention, the facially amphiphilicpolymer(s) or oligomer(s) of the compositions are solubilized at leastin part by an ophthalmically acceptable solubilizing agent. The term“solubilizing agent” herein includes agents that result in formation ofa micellar solution or a true solution of the drug. Certainophthalmically acceptable nonionic surfactants, for example polysorbate80, can be useful as solubilizing agents, as can ophthalmicallyacceptable glycols, polyglycols, e.g., polyethylene glycol 400(PEG-400), and glycol ethers.

Particularly preferred solubilizing agents for solution andsolution/suspension compositions of the invention are cyclodextrins.Suitable cyclodextrins can be selected from α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, alkylcyclodextrins (e.g.,methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin),hydroxyalkylcyclodextrins (e.g., hydroxyethyl-β-cyclodextrin,hydroxypropyl-β-cyclodextrin), carboxy-alkylcyclodextrins (e.g.,carboxymethyl-β-cyclodextrin), sulfoalkylether cyclodextrins (e.g.,sulfobutylether-β-cyclodextrin), and the like. Ophthalmic applicationsof cyclodextrins have been reviewed in Rajewski et al., Journal ofPharmaceutical Sciences, 1996, 85, 1155-1159.

An ophthalmically acceptable cyclodextrin can optionally be present inan ophthalmic composition of the invention at a concentration of about 1to about 200 mg/ml, preferably about 5 to about 100 mg/ml and morepreferably about 10 to about 50 mg/ml.

In some embodiments, the ophthalmic composition optionally contains asuspending agent. For example, in those embodiments in which theophthalmic composition is an aqueous suspension or solution/suspension,the composition can contain one or more polymers as suspending agents.Useful polymers include water-soluble polymers such as cellulosicpolymers, for example, hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. However, preferred ophthalmic compositions of the invention donot contain substantial amounts of solid particulate matter, whether ofthe anti-microbial polymer or oligomer active agent, an excipient, orboth, as solid particulate matter, if present, can cause discomfortand/or irritation of a treated eye.

One or more ophthalmically acceptable pH adjusting agents and/orbuffering agents can be included in the ophthalmic compositions of theinvention, including acids such as acetic, boric, citric, lactic,phosphoric and hydrochloric acids; bases such as sodium hydroxide,sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodiumlactate and tris-hydroxymethylaminomethane; and buffers such ascitrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids,bases and buffers are included in an amount required to maintain pH ofthe composition in an ophthalmically acceptable range.

One or more ophthalmically acceptable salts can be included in thecompositions of the invention in an amount required to bring osmolalityof the composition into an ophthalmically acceptable range. Such saltsinclude, but are not limited to, those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; preferred saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate, with sodium chloride being especiallypreferred.

Optionally an ophthalmically acceptable xanthine derivative such ascaffeine, theobromine or theophylline can be included in thecompositions of the invention, e.g., as disclosed in U.S. Pat. No.4,559,343. Inclusion of the xanthine derivative can reduce oculardiscomfort associated with administration of the composition.

Optionally one or more ophthalmically acceptable surfactants, preferablynonionic surfactants, or co-solvents can be included in the compositionsof the invention to enhance solubility of the components of thecompositions or to impart physical stability, or for other purposes.Suitable nonionic surfactants include, but are not limited to,polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylenealkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40;polysorbate 20, 60 and 80; polyoxyethylene/polyoxypropylene surfactants(e.g., Pluronic® F-68, F84 and P-103); cyclodextrin; or other agentsknown to those of skill in the art. Typically, such co-solvents orsurfactants are employed in the compositions at a level of from about0.01% to about 2% by weight.

One or more ophthalmic lubricating agents can also be includedoptionally in the compositions of the invention to promote lacrimationor as a “dry eye” medication. Such agents include, but are not limitedto, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, and the like. It will be understood that promotionof lacrimation is beneficial in the present invention only wherelacrimation is naturally deficient, to restore a normal degree ofsecretion of lacrimal fluid. Where excessive lacrimation occurs,residence time of the composition in the eye can be reduced.

Ophthalmic compositions of the present invention typically include acombination of one or more of the optional excipients listed above. Forexample, in some embodiments of the invention, the ophthalmiccomposition can optionally further comprise glycerin in an amount ofabout 0.5% to about 5%, more preferably about 1% to about 2.5%, forexample about 1.5% to about 2%, by weight. Glycerin can be useful toincrease viscosity of the composition and for adjustment of osmolality.Independently of the presence of glycerin, the composition can alsofurther comprise a cyclodextrin, preferablyhydroxypropyl-β-cyclodextrin, in an amount of about 0.5% to about 25% byweight, as a solubilizing agent, and an antimicrobially effective amountof a preservative, e.g., imidazolidinyl urea in an amount of about 0.03%to about 0.5%; methylparaben in an amount of about 0.015% to about0.25%; propylparaben in an amount of about 0.005% to about 0.01%;phenoxyethanol in an amount of about 0.25% to about 1%; disodium EDTA inan amount of about 0.05% to about 0.2%; thimerosal in an amount of0.001% to about 0.15%; chlorobutanol in an amount of about 0.1% to about0.5%; and/or sorbic acid in an amount of about 0.05% to about 0.2%; allby weight.

The otic compositions of the present invention also optionally compriseone or more otically acceptable excipients. Otically acceptableexcipients include, but are not limited to, one or more of thepreservatives, stabilizers, antioxidants, viscosity-enhancing agents,buffering agents, solubilizing agents, surfactants, lubricating agents,or acceptable salts described above, or combinations thereof, asdescribed above for the ophthalmic compositions of the invention.

Thus, for example, in some embodiments, an otic composition of thepresent invention optionally comprises one or more buffering agents,solubilizing agents, and antioxidants, typically in an aqueous solution.In some embodiments, the otic composition further comprises glycerin(e.g., anhydrous glycerin) or propylene glycol as a viscosity-enhancingagent. The otic composition may also comprise a surfactant incombination with the glycerin or propylene glycol to aid in the removalof cerum (ear wax). Sodium bicarbonate may also be used if wax is to beremoved from the ear.

Thus, e.g., in some embodiments, the otic composition of the presentinvention is a sterile aqueous solution comprising one or more of thedisclosed polymers or oligomers, glycerin, sodium bicarbonate, and,optionally, a preservative, in purified water.

The ophthalmic and otic compositions of the present invention can beprepared by methods known in the art and described in patents andpublications cited herein and incorporated herein by reference.

Methods of Treatment and Administration

The ophthalmic or otic compositions of the present invention possessanti-microbial activity and can be used in methods of treating orpreventing ophthalmic infections in an eye of an animal, or oticinfections in the ear of an animal.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.Preferably, the animal is a warm-blooded, mammalian subject, including,but not limited to, domestic, farm and exotic mammals, and humans. Themethods of the present invention can be useful, for example, in thetreatment of eye infections in dogs, cats, horses, cattle, sheep and/orpigs, but is more particularly useful where the subject is human.

The phrases “treating an ophthalmic infection” and “treatment of anophthalmic infection” refer to both the prevention and the therapeutictreatment, e.g., the alleviation or amelioration, of an ophthalmicinfection, wherein the object is to prevent or slow down (lessen) theprogress of an ophthalmic infection, or obtain beneficial or desiredclinical results. For example, “beneficial or desired clinical results”include, but are not limited to, alleviation of the symptoms of anophthalmic infection; diminishment of the extent of an ophthalmicinfection; stabilization (for example, not worsening) of the state of anophthalmic infection; delay in the onset or the slowing of an ophthalmicinfection or its progression; amelioration of an ophthalmic infection orremission (whether partial or total), whether detectable orundetectable, or enhancement or improvement of an ophthalmic infection.Treatment includes eliciting a clinically significant response withoutexcessive levels of side effects.

Similarly, the phrases “treating an otic infection” and “treatment of anotic infection” refer to both the prevention and the therapeutictreatment, e.g., the alleviation or amelioration, of an otic infection,wherein the object is to prevent or slow down (lessen) the progress ofan otic infection, or obtain beneficial or desired clinical results. Forexample, “beneficial or desired clinical results” include, but are notlimited to, alleviation of the symptoms of an otic infection;diminishment of the extent of an otic infection; stabilization (forexample, not worsening) of the state of an otic infection; delay in theonset or the slowing of an otic infection or its progression;amelioration of an otic infection or remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of an otic infection. Treatment includes eliciting aclinically significant response without excessive levels of sideeffects.

Ophthalmic infections for which the compositions and methods of thepresent invention are useful include, but are not limited to, infectionsof one or more tissues of the eye, including, for example,conjunctivitis, keratitis (including ulcerative keratitis with bacterialinfection), keratoconjunctivitis (including, e.g., keratoconjunctivitissicca (KCS) commonly found in dogs), blepharitis,blepharoconjunctivitis, dacyrocystitis, hordeolum, corneal ulcers,orbital and preseptal cellulitis, and endophthalmitis

In preferred methods of the invention, the infected tissue is one thatis directly bathed by the lacrimal fluid, as in conjunctivitis,keratitis, keratoconjunctivitis, blepharitis, andblepharoconjunctivitis.

The ophthalmic compositions of the present invention may also be usedprophylactically in connection with various ophthalmic surgicalprocedures that create a risk of infection.

Otic infections for which the compositions and methods of the presentinvention are useful include, but are not limited to, otitis externa andotitis media. With respect to the treatment of otitis media, thecompositions of the present invention are primarily useful in caseswhere the tympanic membrane has ruptured or tympanostomy tubes have beenimplanted. The otic compositions may also be used to treat infectionsassociated with otic surgical procedures, such as tympanostomy, or toprevent such infections.

The ophthalmic and otic compositions of the invention are effective inkilling or inhibiting the growth of a broad spectrum of pathogens ormicrobes often associated with ophthalmic and/or otic infections,including a range of bacteria (both gram-postive and gram-negative),fungi and viruses.

For example, the ophthalmic and otic compositions are useful in killingor inhibiting the growth of any of the following clinically relevantocular or otic pathogens, and can be administered topically to treatand/or prevent ophthalmic or otic infections caused by the followingpathogens or mixtures of the following pathogens: Staphylococcus spp.(e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcusspp. (e.g., Streptococcus viridans, Streptococcus pneumoniae),Enterococcus spp., Bacillus spp., Corynebacterium spp.,Propionibacterium spp., Chlamydia spp., Moraxella spp. (e.g., Moraxellalacunata and Moraxella catarrhalis), Haemophilus spp. (e.g., Haemophilusinfluenza and Haemophilus aegyptius), Pseudomonas spp. (e.g.,Pseudomonas aeruginosa, and, for otic infections, Pseudomonas otitidis),Serratia spp. (e.g., Serratia marcescens), Neisseria spp., andMycoplasma spp., as well as Enterobacter spp. (e.g., Enterobacteraerogenes), Eschericia spp. (e.g., Eschericia coli), Klebsiella spp.(e.g., Klebsiella pneumoniae), Proteus spp. (e.g., Proteus mirabillisand Proteus vulgaris), Acinetobacter spp. (e.g., Acinetobactercalcoaceticus), Prevotella spp., Fusobacterium spp., Porphyromonas spp.,and Bacteroides spp. (e.g., Bacteroides fragilis). This list of microbesis purely illustrative and is in no way to be interpreted asrestrictive.

Thus, for example, the ophthalmic compositions of the present inventioncan be administered to treat or prevent a bacterial infection of the eyecaused by one or more of the following species: Staphylococcus aureus,Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcuspyogenes, Streptococcus viridans, Enterococcus faecalis, Corynebacteriumspp., Propionibacterium spp., Moraxella catarrhalis and Haemophilusinfluenzae.

For example, treatment of bacterial conjunctivitis by administering anophthalmic composition of the present invention is appropriate whereinfection with one or more of the following species is present:Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspneumoniae, Streptococcus pyogenes, Streptococcus viridans, Enterococcusfaecalis, Corynebacterium spp., Propionibacterium spp., Moraxellacatarrhalis and Haemophilus influenzae.

Similarly, treatment of bacterial blepharitis by administering anophthalmic composition of the present invention is appropriate whereinfection with one or more of the following species is present:Staphylococcus aureus, Staphylococcus epidermidis and Streptococcuspneumoniae. Treatment of bacterial keratitis by administering anophthalmic composition of the present invention is also appropriatewhere infection with one or more of the following species is present:Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspneumoniae and Streptococcus viridans.

The otic compositions of the present invention, for example, can also beadministered to treat or prevent a bacterial infection of the ear causedby one or more of the following species: Pseudomonas aeruginosa,Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspneumoniae, Moraxella catarrhalis, Pseudomonas otitidis, and Proteusspp. (e.g., Proteus mirabillis and Proteus vulgaris), as well as one ormore of the following anaerobes: Prevotella spp., Fusobacterium spp.,Porphyromonas spp., and Bacteroides spp. (e.g., Bacteroides fragilis).Thus, for example, treatment of chronic suppurative otitis media byadministering an otic composition of the present invention isappropriate where infection with one or more of the following species ispresent: Staphylococcus aureus, Pseudomonas aeruginosa, Eschericia coli,Klebsiella spp. (e.g., Klebsiella pneumoniae), Proteus spp. (e.g.,Proteus mirabillis and Proteus vulgaris), Prevotella spp., Fusobacteriumspp., Porphyromonas spp., and Bacteroides spp. (e.g., Bacteroidesfragilis).

The ophthalmic or otic compositions are also useful in killing orinhibiting the growth of clinically relevant ocular or otic fungi, andcan be administered topically to treat and/or prevent ophthalmic or oticinfections caused by one or more species of fungi, or a mixture ofspecies of fungi, including, but not limited to, Aspergillus spp. (e.g.,Aspergillus fumigatus, Aspergillus favus, Aspergillus niger andAspergillus terreus), Fusarium spp. (e.g., Fusarium solani, Fusariummoniliforme and Fusarium proliferartum), Malessezia spp. (e.g.,Malessezia pachydermatis), and/or Candida spp. (e.g., Candida albicans),as well as Chrysosporium parvum, Metarhizium anisopliae, Phaeoisariaclematidis, and Sarcopodium oculorum. This list of microbes is purelyillustrative and is in no way to be interpreted as restrictive.

Thus, the ophthalmic compositions of the present invention can beadministered to treat or prevent a fungal infection of the eye caused byone or more of the following species: Aspergillus spp., Fusarium spp.,Chrysosporium parvum, Metarhizium anisopliae, Phaeoisaria clematidis,and Sarcopodium oculorum. For example, the ophthalmic composition can beadministered to treat fungal keratitis caused by one or more Aspergillusspp. and/or Fusarium spp.

The otic compositions of the present invention, for example, can also beadministered to treat or prevent a fungal infection of the ear caused byone or more of the following species: Candida spp., Aspergillus spp.,and/or Malessezia spp. (e.g., Malessezia pachydermatis).

The ophthalmic or otic compositions are also useful in killing orinhibiting the growth of clinically relevant ocular or otic viruses andcan be administered topically to treat and/or prevent ophthalmic or oticinfections caused by one or more viruses, including, but not limited to,adenoviruses and herpes viruses (including, e.g., Herpes simplex 1 virusand/or varicella-zoster virus), Eneroviruses and Cytomegaloviruses.

Thus, for example, the ophthalmic compositions of the present inventioncan be administered to treat or prevent a viral infection of the eye,e.g., Herpes keratitis, caused by Herpes simplex 1 virus.

In some embodiments, the ophthalmic or otic compositions of theinvention are useful and effective in killing and/or preventing thegrowth of microbes that have developed significant levels of resistanceto anti-microbial agents other than the disclosed polymers andoligomers. For example, in some embodiments, the ophthalmic compositionsand otic compositions are especially effective in methods of treatingophthalmic infections or otic infections cased by bacterial strains thathave developed resistance to ciprofloxacin, e.g., CiprofloxacinResistant (CR)S. aureus and CR S. epidermidis, or to fluoroquinolone, orbacterial strains that have developed resistance to penicillin.

In some embodiments, the compositions of the invention are administeredtopically to one or more tissues of the eye or ear to treat an existingmicrobial infection, or as a prophylactic measure to prevent a microbialinfection.

Thus, for example, in some embodiments, an ophthalmic composition of thepresent invention is administered topically to one or more tissues ofthe eye to treat an existing microbial infection, e.g., conjunctivitis,keratitis, blepharitis, or blepharoconjunctivitis.

In other embodiments, an ophthalmic composition of the present inventionis administered topically to one or more tissues of the eye as aprophylactic measure. That is, the compositions are administered forprophylactic uses, e.g., in connection with various ophthalmic surgicalprocedures that create a risk of infection. Thus, for example, acomposition of the invention can be administered in a method ofpost-traumatic prophylaxis, especially post-surgical prophylaxis, toprevent infection after ocular surgery, or in a method of prophylaxisprior to ocular surgery, for example, administered prior to surgery toprevent infection as a consequence of surgery.

The ophthalmic and otic compositions of the present invention possessbroad-spectrum anti-microbial activity due to the facially amphiphilicand cationic properties of the facially amphiphilic polymers andoligomers in the compositions. As a consequence, an ophthalmic infectionor an otic infection can be treated or prevented by administering onlyone of the compositions of the present invention, rather than byadministering two or more separate antimicrobial compositions or oneantimicrobial composition containing a combination of antimicrobialagents.

For example, because the ophthalmic compositions of the invention can beused to treat or prevent both viral and bacterial ophthalmic infectionsin an eye, only one of the present compositions needs to be administeredto the eye to treat a viral ophthalmic infection where there is a riskof a secondary bacterial infection. Similarly, for an eye infectioncaused by multiple strains of bacteria (e.g., by both gram-positivebacteria and gram-negative bacteria), only one composition containingone of the disclosed amphiphilic oligomers needs to be administered,rather than a composition containing multiple anti-microbial agents, ora combination of separate treatments administered concurrently.

In some embodiments, the ophthalmic or otic compositions of the presentinvention are administered with an additional anti-microbial agent, suchas, e.g., an anti-bacterial, anti-fungal, or anti-viral agent. Forexample, the additional anti-microbial agent can be a second faciallyamphiphilic polymer or oligomer disclosed herein, or the additionalanti-microbial agent can be another anti-microbial agent such as, forexample, an antibiotic selected from the group consisting ofaminoglycosides, cephalosporins, diaminopyridines, fluoroquinolones,sulfonamides and tetracyclines. Examples of useful antibiotics which canserve as additional anti-microbials include, but are not limited to,amikacin, azithromycin, cefixime, cefoperazone, cefotaxime, ceftazidime,ceftizoxime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin,colistin, domeclocycline, doxycycline, erythromycin, gentamicin,mafenide, methacycline, minocycline, neomycin, norfloxacin, ofloxacin,oxytetracycline, polymyxin B, pyrimethamine, silver sulfadiazine,sulfacetamide, sulfisoxazole, tetracycline, tobramycin, andtrimethoprim.

In those embodiments in which the ophthalmic or otic composition isadministered with another anti-microbial agent, the present inventionprovides a method of treating or preventing multiple bacterialinfections in an eye or an ear, the method comprising application to theeye or ear in co-therapy (including co-formulation) one or more faciallyamphiphilic polymers or oligomers disclosed herein and one or moreadditional anti-microbial agents. “Co-therapy” herein meansadministration to the eye or ear, at the same time or sequentially, ofan ophthalmically or otically acceptable composition comprising one ormore of the facially amphiphilic polymers or oligomers disclosed hereinand a separate ophthalmically or otically acceptable composition of theadditional anti-microbial agent, in a treatment regimen intended toprovide a beneficial effect from co-action of the two types ofantimicrobial agents. “Co-formulation” herein means that the faciallyamphiphilic polymer or oligomer active agent and the additionalanti-microbial agent are administered to the eye or ear as components ofa single ophthalmically or otically acceptable composition.

The ophthalmic or otic compositions of the present invention also can beused in co-therapy with one or more drugs, or medicaments, other thananti-microbial agents. Such medicaments other than anti-microbial agentscan be co-administered to the eye or ear together with a composition ofthe invention. Thus, e.g., an ophthalmic composition of the presentinvention can further comprise, in co-formulation with the faciallyamphiphilic polymer or oligomer active agent, a therapeutically and/orprophylactically effective amount of one or more medicaments that areother than anti-microbial agents.

These additional medicaments other than anti-microbial agents cancooperate with the anti-microbial facially amphiphilic polymer oroligomer active agent(s) in treating and/or preventing an infectivedisease of the eye or ear, or can be used to treat a related orunrelated condition simultaneously affecting the eye or ear.

Any medicament having utility in an ophthalmic or otic application canbe used in co-therapy, co-administration or co-formulation with anophthalmic or otic composition of the present invention as describedabove. Such additional medicaments include, but are not limited to,anti-inflammatory agents (e.g., steroidal anti-inflammatory agents,non-steroidal anti-inflammatory agents (NSAIDs), and selectivecyclooxygenase-2 inhibitors); topical and/or regional anesthetic agents;anti-allergic agents (e.g., anti-histamines); demulcents; acetylcholineblocking agents; adrenergic agonists, beta-adrenergic blocking agentsand other anti-glaucoma agents; anti-hypertensives; and anti-cataractagents.

For example, ophthalmic and otic infections are frequently accompaniedby inflammation of the infected ophthalmic and/or otic tissues andsurrounding tissues. In addition, ophthalmic and otic surgicalprocedures that create a risk of microbial infections frequently alsocauses inflammation of the affected tissues. Thus, the ophthalmic andotic compositions of the present invention can be co-formulated with ananti-inflammatory agent to combine the anti-infective activity of one ormore antibiotics with the anti-inflammatory activity of one or moresteroid or non-steroid agents in a single composition.

The anti-inflammatory agents can be steroidal or non-steroidal. Examplesof suitable steroidal anti-inflammatory agents include, but are notlimited to, dexamethasone; dexamethasone derivatives such as thosedisclosed in U.S. Pat. No. 5,223,492; rimexolone; prednisolone;fluorometholone; and hydrocortisone.

Examples of suitable non-steroidal anti-inflammatory agents include, butare not limited to, prostaglandin H synthetase inhibitors (Cos I or CoxII), also referred to as cyclooxygenase type I and type II inhibitors,such as diclofenac, flurbiprofen, ketorolac, suprofen, nepafenac,amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen,meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal,oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac,phenylbutazone, aspirin, oxyphenbutazone, tenoxicam and carprofen;cyclooxygenase type II selective inhibitors, such as vioxx, celecoxib,etodolac; PAF antagonists, such as apafant, bepafant, minopafant,nupafant and modipafant; PDE IV inhibitors, such as ariflo,torbafylline, rolipram, filaminast, piclamilast, cipamfylline, androflumilast; inhibitors of cytokine production, such as inhibitors ofthe NFkB transcription factor; or other anti-inflammatory agents know tothose skilled in the art.

Examples of suitable topical or regional anesthetic agents include, butare not limited to, benzocaine.

Examples of suitable anti-allergic agents include, but are not limitedto, pemirolast, olopatadine, and the corticosteroids (prednisolone,fluorometholone, loteprenol and dexamthasone).

The additional medicament can be administered in co-therapy (includingco-formulation) with the one or more facially amphiphilic polymers ofthe ophthalmic or otic composition. For example, in some embodiments, anophthalmic composition of the present invention comprising one of theanti-microbial oligomer disclosed herein is administered in co-therapywith an anti-inflammatory agent, e.g., a glucocorticoid. Theglucocorticoid can be co-formulated with the oligomer in a singleophthalmically acceptable composition, which is administered to one ormore tissues of an eye, to not only treat or prevent an ophthalmicinfection but also to treat and/or prevent inflammation.

The ophthalmic or otic compositions can be administered by anyappropriate route of administration. In some aspects of the invention,the ophthalmic and otic compositions are administered topically, forexample, the composition is topically administered in an antimicrobiallyeffective amount to one or more tissues of the eye of the animal, or toone or more tissues of the ear of an animal.

An appropriate dosage, frequency and duration of administration, forexample, treatment regimen, to be used in any particular situation willbe readily determined by one of skill in the art without undueexperimentation, and will depend, among other factors, on the particularpolymer(s) or oligomer(s) present in the composition, on the particularophthalmic infection being treated, on the age, weight and generalphysical condition of the subject, and on other medication beingadministered to the subject. It is preferred that response of theophthalmic or otic infection to treatment according to the presentmethods be monitored and the treatment regimen be adjusted if necessaryin light of such monitoring.

Frequency of administration is typically such that the dosing interval,for example, the period of time between one dose and the next, duringwaking hours is about 2 to about 12 hours, more typically about 3 toabout 8 hours, for example about 4 to about 6 hours. It will beunderstood by those of skill in the art that an appropriate dosinginterval is dependent to some degree on the length of time for which theselected composition is capable of maintaining a concentration of theanti-microbial polymer(s) or oligomer(s) in the lacrimal fluid and/or inthe target tissue (e.g., the conjunctiva) above the MIC₉₀ (the minimumconcentration of the oligomer or polymer which inhibits microbial growthby 90%). Ideally the concentration remains above the MIC₉₀ for at least100% of the dosing interval. Where this is not achievable it is desiredthat the concentration should remain above the MIC₉₀ for at least about60% of the dosing interval, in a worst case at least about 40% of thedosing interval.

For example, in some embodiments of the ophthalmic compositions of theinvention, the ophthalmic composition is formulated as an in situgellable aqueous liquid and is administered as eye drops. Typically eachdrop, generated by a conventional dispensing means, has a volume ofabout 10 to about 40 μL. From 1 to about 6 such drops typically providesa suitable dose of the oligomer active agent in about 25-1500_, of thecomposition. For example, preferably no more than 3 drops, morepreferably no more than 2 drops, and most preferably no more than 1drop, should contain the desired dose of the active agent foradministration to an eye. Where the composition is administered in aform other than eye drops, for example, as an ophthalmic ointment or asa solid implant, an equivalent dose is provided. Such a dose can beadministered as needed, but typically administration to the eye 1 toabout 6 times per day, in most cases 2 to 4 times a day, providesadequate continuing relief or prevention of the infective diseaseindicated.

The ophthalmic compositions of the invention, e.g., the aqueoussuspension compositions, can be packaged in single-dose non-reclosablecontainers. Such containers can maintain the composition in a sterilecondition and thereby eliminate need for preservatives such asmercury-containing preservatives, which can sometimes cause irritationand sensitization of the eye. Alternatively, multiple-dose reclosablecontainers can be used, in which case it is preferred to include apreservative in the composition.

For example, in some embodiments, the ophthalmic composition is anaqueous solution, suspension or solution/suspension which isadministered in the form of eye drops. In these embodiments, a desireddosage of the active agent can be administered by means of a suitabledispenser as a known number of drops into the eye. Examples of suitabledispensers are disclosed in International Patent Publication No. WO96/06581.

The following examples will serve to further typify the nature of thisinvention but should not be construed as a limitation in the scopethereof, which scope is defined solely by the appended claims. In orderthat the invention disclosed herein may be more efficiently understood,examples are provided below. It should be understood that these examplesare for illustrative purposes only and are not to be construed aslimiting the invention in any manner.

EXAMPLES Example 1 Antimicrobial Activity—Minimum InhibitoryConcentrations

The following three oligomers of the invention were screened forantimicrobial activity against a number of clinically relevant ocularpathogens.

Minimum Inhibitory Concentrations (MIC) of each of the 3 oligomers weredetermined using standard procedures for clinical ocular isolates ofCiprofloxacin Susceptible (CS) S. aureus (CSSA) (n=27), CiprofloxacinResistant (CR)S. aureus (CRSA) (n=28), CS S. epidermidis (CSSE) (n=26),CR S. epidermidis (CRSE) (n=26), St. pneumoniae (SP) (n=27), St.viridans group (SV), Moraxella Species (MS) (n=25), H. influenzae (HI)(n=26), P. aeruginosa (PA) (n=26), and Serratia marcescens (SM) (n=27).

The results are presented in Table 1. Data is expressed as MIC₅₀, MIC₉₀,in μg/ml for Oligomer 1, Oligomer 2, and Oligomer 3, respectively.

TABLE 1 Oligomer 1 Oligomer 2 Oligomer 3 Microbial MIC₅₀ MIC₉₀ MIC₅₀MIC₉₀ MIC₅₀ MIC₉₀ Strain (μg/ml) (μg/ml) (μg/ml) (μg/ml) (μg/ml) (μg/ml)CSSA 0.125 0.25 0.125 0.25 0.5 0.5 CRSA 0.25 0.25 0.25 0.25 0.5 0.5 CSSE0.03 0.125 0.03 0.03 0.25 0.25 CRSE 0.03 0.03 0.03 0.03 0.25 0.25 SP 0.51 1 2 2 2 SV 4 16 4 32 4 8 MS 0.5 0.5 0.25 0.5 1 2 HI 16 32 8 16 4 8 PA4 8 4 8 4 4 SM 16 64 16 32 64 256 Oligomers 1, 2, and 3 demonstratedbroad spectrum in vitro activity against a number of clinically relevantocular pathogens.

Example 2 Ophthalmic Ointment Formulation

The following represents an example of a typical ophthalmic ointmentformulation comprising an antimicrobial oligomer of the invention(oligomer 1 in Example 1 above).

Ophthalmic Ointment

Ingredient Amount (weight %) Oligomer 1 0.35 Mineral Oil, USP 2.0 Whitepetrolatum, USP q.s. 100

Example 3 Ophthalmic Ointment Formulation

The following represents an example of a typical ophthalmic ointmentformulation comprising an antimicrobial oligomer of the invention(oliogmer 2 in Example 1 above) and an anti-inflammatory agent.

Ophthalmic Ointment

Ingredient Amount (weight %) Oligomer 2 0.3 Dexamethasone 0.1Chlorobutanol, Anhydrous, NF 0.5 Mineral Oil, USP 5.0 White petrolatum,USP q.s. 100

Example 4 Ophthalmic/Otic Solution Formulation

The following represents an example of a typical ophthalmic/oticsolution formulation comprising an antimicrobial oligomer of theinvention (oliogmer 3 in Example 1 above).

Ophthalmic/Otic Solution

Ingredient Amount (weight %) Oligomer 3 0.35 Sodium Acetate 0.3 AceticAcid 0.04 Mannitol 4.60 EDTA 0.05 Benzalkonium chloride 0.006 Water q.s.100

Example 5 Ophthalmic/Otic Suspension Formulation

The following represents an example of a typical ophthalmic/oticsuspension formulation comprising an antimicrobial oligomer of theinvention (oliogmer 3 in Example 1 above) and an anti-inflammatory agent(dexamethasone).

Ophthalmic/Otic Suspension

Ingredient Amount (weight %) Oligomer 3 0.3 Dexamethasone, micronizedUSP 0.10 Benzalkonium chloride 0.01 Edetate Disodium USP 0.01 Sodiumchloride USP 0.3 Sodium sulfate USP 1.2 Tyloxapol USP 0.05Hydroxyethylcellulose 0.25 Sulfuric Acid and/or q.s. for pH adjustmentto 7.0-8.0 Sodium hydroxide, NF Purified sterilized water q.s. to 100

Example 6 Toxicity

The ocular toxicity of several concentrations of Oligomer 2, using theDraize ocular toxicity scoring system, in the NZW rabbit ocular toxicitymodel was carried out.

Nine rabbits were received from Myrtles' Rabbitry, Thompson Station,Tenn. and were subsequently divided into 5 groups:

Oligomer 2 N N Rabbit Group Concentration Rabbits Eyes Numbers I   1%Oligomer 2 2 4 1-2 II 0.25% Oligomer 2 2 4 3-4 III  0.1% Oligomer 2 2 45-6 IV 0.01% Oligomer 2 2 4 7-8 V Tris-Buffered Saline 1 2 9Rabbits were treated in both eyes with (37 μl) topical drops every 30minutes for 3 hours (7 total doses). One rabbit was treated withTris-Buffered Saline and served as a negative control. Rabbits wereevaluated in a masked fashion for ocular toxicity by an ophthalmologistwith specialty training in corneal and external disease. Ocular toxicitywas evaluated using the Draize scoring system after treatment on Day 0and on Day 3 post treatment for any delayed toxicity. (Draize et al., J.Pharmacol. Exp. Ther., 1944, 82, 377-390).

IACUC Protocol #0701145 “The In Vivo Evaluation of Biomimetics asTopical

Ocular Antibiotics”. Formulations: 1) 1% Oligomer 2: 31.36 mg ofOligomer 2 in powder form was stored at −20° C. until use. The vialcontaining Oligomer 2 was removed from the freezer and 3.126 ml ofTris-Buffered Saline (TBS) was added to the vial to yield 3.126 ml of 1%(10 mg/ml) Oligomer 2; 2) 0.25% Oligomer 2: 0.5 ml of 1% Oligomer 2 wasadded to 1.5 ml of TBS to yield 2 ml of 0.25% Oligomer 2; 3) 0.1%Oligomer 2: 0.2 ml of 1% Oligomer 2 was added to 1.8 ml of TBS to yield2 ml of 0.1% Oligomer 2; 4) 0.01% Oligomer 2: 0.2 ml of 0.1% Oligomer 2was added to 1.8 ml of TBS to yield 2 ml of 0.01% Oligomer 2; and 5)Tris-Buffered Saline: 25 ml of Tris-Buffered Saline (10 mM TRIS, 150 mMNaCl, pH=7.4) was filter sterilized prior to use in preparation of theabove samples and use in rabbits. The following schedule was adhered to.

Ocular Toxicity Evaluation Drop Schedule Group I Group II Group IIIGroup IV 1% 0.25% 0.1% 0.01% Elapsed Time of Oligomer Oligomer OligomerOligomer Group V Drop Time Day 2 2 2 2 TBS 1 0 11:40 am X X X X X 2  :3012:10 pm X X X X X 3 1:00 12:40 pm X X X X X 4 1:30  1:10 pm X X X X X 52:00  1:40 pm X X X X X 6 2:30  2:10 pm X X X X X 7 3:00  2:40 pm X X XX X Examine 3:20  3:00 pm X X X X X

A brief summary of the Draize scoring system for ocular lesions isprovided below

1. Cornea

A. Opacity-degree of density (area most dense taken for reading) NoOpacity 0 Scattered or diffuse area, details of iris clearly visible 1Easily discernible translucent areas, details of iris slightly obscured2 Opalescent areas, no details of iris visible, size of pupil barely 3discernible Opaque, iris invisible 4 B. Area of cornea involved Onequarter (or less) but not zero 1 Greater than one quarter, but less thanhalf 2 Greater than half, but less than three quarters 3 Greater thanthree quarters, up to whole area 4 A × B × 5 Total Maximum = 80

2. Iris

A Values Normal 0 Folds above normal, congestion, swelling,circumcorneal injection 1 (any or all of these or combination of anythereof) iris still reacting to light (sluggish reaction is positive) Noreaction to light, hemorrhage, gross destruction (any or all of 2 these)A × 5 Total Maximum = 10

3. Conjunctivae

A. Redness (refers to palpebral and bulbar conjunctivas excluding corneaand iris) Vessels normal 0 Vessels definitely injected above normal 1More diffuse, deeper crimson red, individual vessels not easily 2discernible Diffuse beefy red 3 B. Chemosis No swelling 0 Any swellingabove normal (includes nictitating membrane) 1 Obvious swelling withpartial eversion of lids 2 Swelling with lids about half-closed 3Swelling with lids about half-closed to completely closed 4 C. DischargeNo discharge 0 Any amount different from normal (does not include 1small amounts observed in inner canthus of normal animals) Dischargewith moistening of the lids and hairs just 2 adjacent to lids Dischargewith moistening of the lids and hairs, and 3 considerable area aroundthe eye Score (A + B + C) × 2 Total Maximum = 20Total Maximum Score: 110 represents the sum of all scores obtained forthe cornea, iris and conjunctivae.

Classification of Eye Irritation Scores:

MMTS Classification Symbol 0.0-0.5 Non-Irritating N 0.6-2.5 PracticallyNon-Irritating PN  2.6-15.0 Minimally Irritating M1 15.1-25.0 MildlyIrritating M2 25.1-50.0 Moderately Irritating M3 50.1-80.0 SeverelyIrritating S  80.1-100.0 Extremely Irritating E 100.1-110.0 MaximallyIrritating Mx MMTS = Maximum Mean Total Score (The mean total score pergroup) Kay et al., J. Soc. Cos. Chem., 1962, 13, 281-289.

Acute Ocular Toxicity Evaluation Observations of Rabbit Behavior AfterInstillation of Test Drugs on Day 0:

Oligomer 2 Group Concentration I   1% Oligomer 2 II 0.25% Oligomer 2 III 0.1% Oligomer 2 IV 0.01% Oligomer 2 V Tris-Buffered Saline

Drop 1 (11:40 am)

No adverse behavior observed after instillation of ALL test drugs.

Drop 2 (12:10 pm)

No adverse behavior observed after instillation of ALL test drugs.

Drop 3 (12:40 pm)

No adverse behavior observed after instillation of ALL test drugs.

-   -   Group I-1% Oligomer 2—Eyes have developed noticeable        conjunctivitis.

Drop 4 (1:10 pm)

No adverse behavior observed after instillation of ALL test drugs.

-   -   Group I-1% Oligomer 2—Eyes have developed noticeable discharge.

Drop 5 (1:40 pm)

No adverse behavior observed after instillation of ALL test drugs.

Drop 6 (2:10 pm)

No adverse behavior observed after instillation of ALL test drugs.

Drop 7 (2:40 pm)

No adverse behavior observed after instillation of ALL test drugs.

Group: I 1% Oligomer 2 Day 0 Day 3 Test/Eye 1L 1R 2L 2R 1L 1R 2L 2R I.A.  0  0  0  0 0 0 0 0 I. B.  0  0  0  0 0 0 0 0 I. Tot  0  0  0  0 0 00 0 II. A.  1  1  1  1 0 0 0 0 II. Tot  5  5  5  5 0 0 0 0 III. A.  2  2 1  1 0 0 0 0 III. B.  2  2  1  2 0 0 0 0 III. C.  3  2  3  2 0 0 0 0III. Tot 14 12 10 10 0 0 0 0 Score 19 17 15 15 0 0 0 0 MMTS 16.5 - M₂0.0 - N

Group: II 0.25% Oligomer 2 Day 0 Day 3 Test/Eye 3L 3R 4L 4R 3L 3R 4L 4RI. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II.A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 1 2 1 0 0 0 0 0 III.B. 1 1 0 0 0 0 0 0 III. C. 2 1 1 0 0 0 0 0 III. Tot 8 8 4 0 0 0 0 0Score 8 8 4 0 0 0 0 0 MMTS 5.0 - M₁ 0.0 - N

Group: III 0.1% Oligomer 2 Day 0 Day 3 Test/Eye 5L 5R 6L 6R 5L 5R 6L 6RI. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II.A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 0 0 0 0 0 0 0 0 III.B. 0 0 0 0 0 0 0 0 III. C. 0 0 0 0 0 0 0 0 III. Tot 0 0 0 0 0 0 0 0Score 0 0 0 0 0 0 0 0 MMTS 0.0 - N 0.0 - N

Group: IV 0.01% Oligomer 2 Day 0 Day 3 Test/Eye 7L 7R 8L 8R 7L 7R 8L 8RI. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II.A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 0 0 1 0 0 0 1 0 III.B. 0 0 0 0 0 0 0 0 III. C. 0 0 0 0 0 0 0 0 III. Tot 0 0 2 0 0 0 2 0Score 0 0 2 0 0 0 2 0 MMTS 0.5 - N 0.5 - N

Group: V TBS Control Day 0 Day 3 Test/Eye 9L 9R 9L 9R I. A. 0 0 0 0 I.B. 0 0 0 0 I. Tot 0 0 0 0 II. A. 0 0 0 0 II. Tot 0 0 0 0 III. A. 0 0 0 0III. B. 0 0 0 0 III. C. 0 0 0 0 III. Tot 0 0 0 0 Score 0 0 0 0 MMTS0.0 - N 0.0 - N

Summary of MMTS Results

Group Day 0 Day 3 1% Oligomer 2 16.5 - M₂ 0.0 - N Mildly IrritatingNon-Irritating 0.25% Oligomer 2 5.0 - M₁ 0.0 - N Minimally IrritatingNon-Irritating 0.1% Oligomer 2 0.0 - N 0.0 - N Non-IrritatingNon-Irritating 0.01% Oligomer 2 0.5 - N 0.5 - N Non-IrritatingNon-Irritating Tris-Buffered Saline 0.0 - N 0.0 - N Non-IrritatingNon-Irritating

Oligomer 2 demonstrated dose dependent ocular toxicity after 7 topicalinstillations (every 30 minutes for 3 hours) in the NZW rabbit oculartoxicity model. 1% Oligomer 2 was determined to be Mildly Irritating,0.25% Oligomer 2 was determined to be Minimally Irritating, while 0.1%and 0.01% Oligomer 2 were determined to be Non-Irritating.

There were no acute reactions by the rabbits (flinching, immediatewiping of eyes, vocalization, hopping to rear of cage) upon instillationof any of the Oligomer 2 concentrations suggesting that Oligomer 2 doesnot sting upon instillation.

There was no prolonged toxicity (3 days after drops) demonstrated in anytreatment group.

1% Oligomer 2, though Mildly Irritating, is suitable for use todetermine whether Oligomer 2 demonstrates efficacy in the Staphylococcusaureus keratitis model.

Example 7 Toxicity

The ocular toxicity of several formulations of Oligomer 4 with andwithout farnesol, using the Draize ocular toxicity scoring system, inthe NZW rabbit ocular toxicity model was carried out.

Fifteen rabbits were received from Myrtles' Rabbitry, Thompson Station,Tenn. and were divided into 8 groups:

N N Rabbit Group Formulation Rabbits Eyes Numbers I 0.25% Oligomer 4 inTris Buffered 2 4 1-2 Saline (TBS) II 0.5% Oligomer 4 Tris Buffered 2 43-4 Saline (TBS) III 100 μM Farnesol in 1% Propylene 2 4 5-6 Glycol (PG)and TBS IV 200 μM Farnesol in 1% Propylene 2 4 7-8 Glycol (PG) and TBS V0.25% Oligomer 4 + 100 μM 2 4  9-10 Farnesol in 1% PG and TBS VI 0.5%Oligomer 4 + 100 μM 2 4 11-12 Farnesol in 1% PG and TBS VII 1% PropyleneGlycol in TBS 2 4 13-14 VIII Tris-Buffered Saline 1 2 15Rabbits were treated in both eyes with (37 μl) topical drops every 30minutes for 3 hours (7 total doses). One rabbit was treated withTris-Buffered Saline and served as a negative control. Rabbits wereevaluated in a masked fashion for ocular toxicity by an ophthalmologistwith specialty training in corneal and external disease 30 minutes afterthe final dose. Ocular toxicity was evaluated using the Draize scoringsystem (see above) after treatment on Day 0 and on Day 2 post treatmentfor any delayed toxicity.

Formulations: 1) 0.25% Oligomer 4: Vial 1 of Oligomer 4 in powder formwas stored at 4° C. until use. The vial was removed from therefrigerator and 1.04 ml of sterile water for injection was added andvortexed until solid was completely dissolved. Then, 1.04 ml of SolutionA (2×TBS) was added and vortexed for 10 seconds; 2) 0.5% Oligomer 4:Vial 2 of Oligomer 4 in powder form was stored at 4° C. until use. Thevial was removed from the refrigerator and 1.04 ml of sterile water forinjection was added and vortexed until solid was completely dissolved.Then, 1.04 ml of Solution A (2×TBS) was added and vortexed for 10seconds; 3) 100 μM Farnesol in 1% Propylene Glycol (PG) and TBS: Vial 3containing about 2 ml of 100 μM Farnesol in 1% Propylene Glycol (PG) andTBS was stored at 4° C. until use; 4) 200 μM Farnesol in 1% PropyleneGlycol (PG) and TBS: Vial 4 containing about 2 ml of 200 μM Farnesol in1% Propylene Glycol (PG) and TBS was stored at 4° C. until use; 5) 0.25%Oligomer 4+100 μM Farnesol in 1% PG and TBS: Vial 5 of Oligomer 4 inpowder form was stored at 4° C. until use; at the time of use, the vialwas removed from the refrigerator and 1.016 ml of sterile water forinjection was added and vortexed until solid was completely dissolved;then 1.016 ml of Solution B (2% PG, 2×TBS, 200 μM Farnesol) was addedand vortexed for 10 seconds; 6) 0.5% Oligomer 4+100 μM Farnesol in 1% PGand TBS: Vial 6 of Oligomer 4 in powder form was stored at 4° C. untiluse; at the time of use, the vial was removed from the refrigerator and1.02 ml of sterile water for injection was added and vortexed untilsolid was completely dissolved; then 1.02 ml of Solution B (2% PG,2×TBS, 200 μM Farnesol) was added and vortexed for 10 seconds; 7) 1%Propylene Glycol in TBS: Vial 7 containing about 2 ml of 1% PropyleneGlycol was stored at 4° C. until use; and 8) Tris-Buffered Saline: Vial8 containing about 2 ml of Tris-Buffered Saline (10 mM TRIS, 150 mMNaCl, pH=7.4) was stored at 4° C. until use.

IACUC Protocol #0701145-1 “The In Vivo Evaluation of Biomimetics asTopical Ocular Antibiotics”.

Ocular Toxicity Evaluation Drop Schedule - Groups Elapsed Time Drop Timeof Day I II III IV V VI VII VIII 1 0 10:45 X X X X X X X X 2  :30 11:15X X X X X X X X 3 1:00 11:45 X X X X X X X X 4 1:30 12:15 X X X X X X XX 5 2:00 12:45 X X X X X X X X 6 2:30  1:15 X X X X X X X X 7 3:00  1:45X X X X X X X X Exam 3:30  2:15 X X X X X X X X

Acute Ocular Toxicity Evaluation

Observations of Rabbit Behavior After Instillation of Test Drugs on Day0

Group Formulation I 0.25% Oligomer 4 in Tris Buffered Saline (TBS) II0.5% Oligomer 4 Tris Buffered Saline (TBS) III 100 μM Farnesol in 1%Propylene Glycol (PG) and TBS IV 200 μM Farnesol in 1% Propylene Glycol(PG) and TBS V 0.25% Oligomer 4 + 100 μM Farnesol in 1% PG and TBS VI0.5% Oligomer 4 + 100 μM Farnesol in 1% PG and TBS VII 1% PropyleneGlycol in TBS VIII Tris-Buffered Saline

Drop 1 (10:45 am)

No adverse behavior observed after instillation of ALL test drugs.

Drop 2 (11:15 am)

No adverse behavior observed after instillation of ALL test drugs.

Drop 3 (11:45 am)

No adverse behavior observed after instillation of ALL test drugs.

Drop 4 (12:15 am)

No adverse behavior observed after instillation of ALL test drugs.

Drop 5 (12:45 pm)

No adverse behavior observed after instillation of ALL test drugs.

Drop 6 (1:15 pm)

No adverse behavior observed after instillation of ALL test drugs.

Drop 7 (1:45 pm)

No adverse behavior observed after instillation of ALL test drugs.

Group: I 0.25% Oligomer 4 Day 0 Day 2 Test/Eye 1L 1R 2L 2R 1L 1R 2L 2RI. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II.A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 0 0 0 0 0 0 0 0 III.B. 0 0 0 0 0 0 0 0 III. C. 0 1 1 1 0 1 0 0 III. Tot 0 2 2 2 0 2 0 0Score 0 2 2 2 0 2 0 0 MMTS 1.5 − PN 0.5 − N Practically Non-IrritatingNon-Irritating

Group: II 0.5% Oligomer 4 Day 0 Day 2 Test/Eye 3L 3R 4L 4R 3L 3R 4L 4RI. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II.A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 1 1 1 0 0 0 0 0 III.B. 1 1 1 0 0 0 0 0 III. C. 2 2 2 1 0 0 1 1 III. Tot 8 8 8 2 0 0 2 2Score 8 8 8 2 0 0 2 2 MMTS 6.5 − M₁ 1.0 − N Minimally PracticallyIrritating Non-Irritating

Group: III 100 μM Farnesol in 1% Propylene Glycol (PG) and TBS Day 0 Day2 Test/Eye 5L 5R 6L 6R 5L 5R 6L 6R I. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 00 0 0 I. Tot 0 0 0 0 0 0 0 0 II. A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 00 0 III. A. 0 0 0 0 0 0 0 0 III. B. 0 0 0 0 0 0 0 0 III. C. 0 0 0 0 1 01 1 III. Tot 0 0 0 0 2 0 2 2 Score 0 0 0 0 2 0 2 2 MMTS 0.0 − N 1.5 − PNNon-Irritating Practically Non-Irritating

Group: IV 200 μM Farnesol in 1% Propylene Glycol (PG) and TBS Day 0 Day2 Test/Eye 7L 7R 8L 8R 7L 7R 8L 8R I. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 00 0 0 I. Tot 0 0 0 0 0 0 0 0 II. A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 00 0 III. A. 0 0 0 0 0 0 0 0 III. B. 0 0 0 0 0 0 0 0 III. C. 0 0 0 1 0 00 1 III. Tot 0 0 0 2 0 0 0 2 Score 0 0 0 2 0 0 0 2 MMTS 0.5 − N 0.5 − NNon-Irritating Non-Irritating

Group: V 0.25% Oligomer 4 + 100 μM Farnesol in 1% PG and TBS Day 0 Day 2Test/Eye 9L 9R 10L 10R 9L 9R 10L 10R I. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 00 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II. A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 00 0 0 III. A. 0 1 0 0 0 0 0 0 III. B. 0 1 0 0 0 0 0 0 III. C. 0 2 1 1 01 1 1 III. Tot 0 8 2 2 0 2 2 2 Score 0 8 2 2 0 2 2 2 MMTS 3.0 − M₁ 1.5 −PN Minimally Practically Irritating Non-Irritating

Group: VI 0.5% Oligomer 4 + 100 μM Farnesol in 1% PG and TBS Day 0 Day 2Test/Eye 11L 11R 12L 12R 11L 11R 12L 12R I. A. 0 0 0 0 0 0 0 0 I. B. 0 00 0 0 0 0 0 I. Tot 0 0 0 0 0 0 0 0 II. A. 0 0 0 0 0 0 0 0 II. Tot 0 0 00 0 0 0 0 III. A. 2 2 2 2 0 0 0 0 III. B. 1 2 1 1 0 0 0 0 III. C. 2 2 22 1 0 1 0 III. Tot 10 12 10 10 2 0 2 0 Score 10 12 10 10 2 0 2 0 MMTS10.5 − M₁ 1.0 − PN Minimally Practically Irritating Non-Irritating

Group: VII 1% Propylene Glycol in TBS Day 0 Day 2 Test/Eye 13L 13R 14L14R 13L 13R 14L 14R I. A. 0 0 0 0 0 0 0 0 I. B. 0 0 0 0 0 0 0 0 I. Tot 00 0 0 0 0 0 0 II. A. 0 0 0 0 0 0 0 0 II. Tot 0 0 0 0 0 0 0 0 III. A. 0 00 0 0 0 0 0 III. B. 0 0 0 0 0 0 0 0 III. C. 0 1 0 0 1 1 0 1 III. Tot 0 20 0 2 2 0 2 Score 0 2 0 0 2 2 0 1 MMTS 0.5 − N 1.5 − PN Non-IrritatingPractically Non-Irritating

Group: VIII TBS Treated Control Day 0 Day 2 Test/Eye 15L 15R 15L 15R I.A. 0 0 0 0 I. B. 0 0 0 0 I. Tot 0 0 0 0 II. A. 0 0 0 0 II. Tot 0 0 0 0III. A. 0 0 0 0 III. B. 0 0 0 0 III. C. 1 1 1 1 III. Tot 2 2 2 2 Score 22 2 2 MMTS 2.0 - PN 2.0 - PN Practically Practically Non-IrritatingNon-Irritating

Summary of MMTS Results

Group Day 0 Day 2 0.25% Oligomer 4 in 1.5 - PN 0.5 - N Tris BufferedSaline Practically Non-Irritating (TBS) Non-Irritating 0.5% Oligomer 4Tris 6.5 - M₁ 1.0 - N Buffered Saline (TBS) Minimally PracticallyIrritating Non-Irritating 100 μM Farnesol in 0.0 - N 1.5 - PN 1%Propylene Glycol Non-Irritating Practically (PG) and TBS Non-Irritating200 μM Farnesol in 0.5 - N 0.5 - N 1% Propylene Glycol Non-IrritatingNon-Irritating (PG) and TBS 0.25% Oligomer 4 + 3.0 - M₁ 1.5 - PN 100 μMFarnesol in Minimally Practically 1% PG and TBS IrritatingNon-Irritating 0.5% Oligomer 4 + 10.5 - M₁ 1.0 - PN 100 μM Farnesol inMinimally Practically 1% PG and TBS Irritating Non-Irritating 1%Propylene Glycol 0.5 - N 1.5 - PN in TBS Non-Irritating PracticallyNon-Irritating Tris-Buffered Saline 2.0 - PN 2.0 - PN PracticallyPractically Non-Irritating Non-Irritating

Oligomer 4 demonstrated dose dependent ocular toxicity after 7 topicalinstillations (every 30 minutes for 3 hours) in the NZW rabbit oculartoxicity model. 0.5% Oligomer 4 was determined to be Mildly Irritating,while 0.25% was determined to be Practically Non-Irritating. Theaddition of 100 μM Farnesol in 1% Propylene Glycol to the Oligomer 4concentrations increased the toxicity of both 0.5% and 0.25% Oligomer 4.Both formulations were determined to be Mildly Irritating. This was thesame category as 0.5% Oligomer 4 alone, but the scores were higher. Thisclassification was an increase for 0.25% Oligomer 4. 100 μM Farnesol,200 μM Farnesol, and 1% Propylene Glycol individually were determined tobe Non-Irritating. Tris-buffered Saline was determined to be PracticallyNon-Irritating. Rabbits demonstrated no adverse behavior uponinstillation of any the test drugs. This indicates all of the test drugsdid not sting upon instillation. There was really no prolonged ordelayed toxicity (2 days after drops) demonstrated in any treatmentgroup. The only finding on Day 2 was a slight discharge in some of theeyes which accounted for all of the scores. Although the completeformulations of 0.5% Oligomer 4 and 0.25% Oligomer 4 (including 100 μMFarnesol and 1% Propylene Glycol) were both classified as MildlyIrritating, the MMTS score for the 0.5% Oligomer 4 formulation was atthe higher end of the classification whereas 0.25% Oligomer 4formulation was at the lower end of the classification. It appears thatthe complete 0.5% Oligomer 4 formulation (including 100 μM Farnesol and1% Propylene Glycol), though Mildly Irritating in uninfected eyes isprobably not as suitable as other formulations for use in the efficacystudies in the Staphylococcus aureus keratitis model. The completeformulation of 0.25% Oligomer 4 (including 100 μM Farnesol and 1%Propylene Glycol) may be acceptable from a toxicity point of view.Experience with other formulations have generally shown that oculartoxicity can increase when instilled more frequently (21 drops vs. 7drops) in infected eyes in the Staphylococcus aureus keratitis efficacymodel.

Example 8 MIC

One purpose of the following experiments was to determine the MICs oftwo biomimetic compounds vs. 25 ocular isolates of Staphylococcus aureusfluoroquinolone-susceptible, Staphylococcus aureusfluoroquinolone-resistant, Staphylococcus epidermidis(Coagulase-negative Staphylococcus) fluoroquinolone-susceptible,Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant, Serratia marcescens, Streptococcuspneumoniae, Streptococcus viridans group, Moraxella species (includingMoraxella catarrhalis) and Pseudomonas aeruginosa and Haemophilusinfluenzae.

General Procedures:

-   Mueller-Hinton Broth in tubes was inoculated with 25 ocular isolates    of Staphylococcus aureus fluoroquinolone-susceptible, Staphylococcus    aureus fluoroquinolone-resistant, Staphylococcus epidermidis    (Coagulase-negative Staphylococcus) fluoroquinolone-susceptible,    Staphylococcus epidermidis (Coagulase-negative Staphylococcus)    fluoroquinolone-resistant, Pseudomonas aeruginosa and Serratia    marcescens, plus two controls (Staphylococcus aureus and E. coli)    and incubated at 37° C. overnight on a shaker set at 250 rpm.

Mueller-Hinton Broth supplemented with 2% lysed horse blood in tubes wasinoculated with 25 ocular isolates of Streptococcus pneumoniae,Streptococcus viridans group, and Moraxella species (including Moraxellacatarrhalis) plus two controls (Staphylococcus aureus and E. coli) andincubated at 37° C. overnight. Additionally, Mueller-Hinton Broth intubes was inoculated with two controls (Staphylococcus aureus and E.coli) and incubated at 37° C. overnight on a shaker set at 250 rpm.

HTM (Haemophilus Test Medium) in tubes was inoculated with 25 ocularisolates of Haemophilus influenzae plus two controls (Staphylococcusaureus and E. coli) and incubated at 37° C. overnight. Additionally,Mueller-Hinton Broth in tubes was inoculated with two controls(Staphylococcus aureus and E. coli) and incubated at 37° C. overnight ona shaker set at 250 rpm.

On the day of testing, a 640 μg/ml (1280 μg/ml for Serratia marcescensand Pseudomonas aeruginosa) concentration was prepared from a 1% stocksolution in 0.01% acetic acid, 0.2% BSA in polypropylene tubes.

Serial doubling dilutions in 0.01% acetic acid, 0.2% BSA in 96 wellpolypropylene plates, which are used as reservoirs for the inoculationof the test plates, were carried out to obtain serial dilutions of testagents at 10 times the required test concentrations: 640, 320, 160, 80,40, 20, 10, 5, 2.5, 1.25, and 0.625 μg/ml (1280, 640, 320, 160, 80, 40,20, 10, 5, 2.5, and 1.25 μg/ml for Serratia marcescens and Pseudomonasaeruginosa).

Ten μl of diluted 10×test agents was added to each well of one row ofthe 96 well polypropylene plates from column 2 to column 12 (column 1 isa control for bacteria alone, with no peptide). Test agentconcentrations in columns 2-12 were as follows: 64, 32, 16, 8, 4, 2, 1,0.5, 0.25, 0.125, and 0.0625 μg/ml (128, 64, 32, 16, 8, 4, 2, 1, 0.5,0.25, and 0.125 μg/ml for Serratia marcescens and Pseudomonasaeruginosa). The same peptide was in each of the 8 rows. One platecontained dilutions of one test agent and 8 bacterial isolates.

On the day of testing, the overnight bacterial broth cultures ofStaphylococcus aureus fluoroquinolone-susceptible, Staphylococcus aureusfluoroquinolone-resistant, Staphylococcus epidermidis(Coagulase-negative Staphylococcus) fluoroquinolone-susceptible,Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant, Serratia marcescens, and Pseudomonasaeruginosa, plus two controls (Staphylococcus aureus and E. coli) werediluted in 5 ml of trypticase soy broth to yield turbidity equal to a0.5 McFarland standard. The final inoculum for MIC testing forStaphylococcus aureus fluoroquinolone-susceptible, Staphylococcus aureusfluoroquinolone-resistant, Staphylococcus epidermidis(Coagulase-negative Staphylococcus) fluoroquinolone-susceptible,Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant, Serratia marcescens, and Pseudomonasaeruginosa was achieved by placing 0.05 ml of the turbidity adjustedsample to 5 ml of Mueller-Hinton broth.

Control Bacteria—The two control bacteria (Staphylococcus aureus and E.coli) were treated as above.

On the day of testing, the overnight bacterial broth cultures ofStreptococcus pneumoniae, Streptococcus viridans and Moraxella species(including Moraxella catarrhalis) plus two controls (Staphylococcusaureus and E. coli) were diluted in 5 ml of trypticase soy broth toyield turbidity equal to a 0.5 McFarland standard. The final inoculumfor MIC testing for Streptococcus pneumoniae, Streptococcus viridans andMoraxella species (including Moraxella catarrhalis) was achieved byplacing 0.1 ml of the turbidity adjusted sample to 5 ml ofMueller-Hinton broth containing 2% lysed horse red blood cells.

Control Bacteria Set #1—this set of control bacteria were treated as theStreptococcus pneumoniae, Streptococcus viridans and Moraxella species(including Moraxella catarrhalis) test isolates above; the controlbacteria underwent the same conditions as the test Streptococcuspneumoniae, Streptococcus viridans and Moraxella species (includingMoraxella catarrhalis) isolates. This set of control bacteria was todetermine whether there was a difference in the MICs by performing theMIC determinations in 2% lysed horse red blood cells with the standardmethod performed in Mueller-Hinton broth.

Control Bacteria Set #2—the control bacteria were added to 5 ml ofMueller-Hinton Broth without the 2% lysed horse red blood cells toachieve the standard inoculum concentration. This set of controlbacteria is the normal control to determine whether the compounds are atthe target MICs.

On the day of testing, the overnight bacterial broth cultures ofHaemophilus species was diluted in 5 ml of trypticase soy broth to yieldturbidity equal to a 0.5 McFarland standard. The final inoculum for MICtesting for Haemophilus species was achieved by placing 0.1 ml of theturbidity adjusted sample to 5 ml of HTM medium.

Control Bacteria Set #1—this set of control bacteria were treated as theHaemophilus influenzae test isolates above; the control bacteriaunderwent the same conditions as the test Haemophilus influenzaeisolates. This set of control bacteria is to determine whether there wasa difference in the MICs by performing the MIC determinations in HTMbroth with the standard method performed in Mueller-Hinton broth.

Control Bacteria Set #2—the control bacteria were added to 5 ml ofMueller-Hinton Broth to achieve the standard inoculum concentration.This set of control bacteria is the normal control to determine whetherthe compounds are at the target MICs.

Ninety μl of the bacterial suspensions was dispensed in each well fromcolumn 1 to column 12. Each bacterial isolate was placed in one row of a96 well polypropylene plate containing the test agents. The plates wereplaced on shaker at 15 minutes at room temperature, and then incubatedat 37° C. overnight. MICs were determined visually as the lowestconcentration of drug that inhibits visible bacterial growth.

The MICs of the 2 compounds Oligomer 4 and Oligomer 5 were comparedstatistically with the Kruskal-Wallis ANOVA with Duncan's MultipleComparisons Test using True Epistat statistical software (True Epistat,Richardson, Tex.).

MIC (ug/mL) Oligomer E. coli D31 S. aureus ATCC27660 Oligomer 4 0.780.098 Oligomer 5 1.56 0.78

MIC E. coli S. aureus E. faecalis P. aeruginosa K. pneumoniae CompoundLab Strain D31 ATCC 27660 ATCC 29212 ATCC 10145 Lab Strain KP10 Oligomer4 0.78 0.098 0.78 12.5 0.78 Oligomer 5 1.56 0.78 1.56 >100 1.56Isolate numbers with a “K” before the number indicates they have beenisolated from cases of Keratitis. Isolate numbers with an “E” before thenumber indicates they have been isolated from cases of Endophthalmitis.Isolate numbers with a “B” before the number indicates they have beenisolated from cases of Blepharitis and or Conjunctivitis. MostStreptococcus pneumoniae isolates are from cases of conjunctivitis.“Fluoroquinolone-resistant” indicates the bacteria are resistant to thesecond generation fluoroquinolones ciprofloxacin and ofloxacin but, notnecessarily resistant to the fourth generation fluoroquinolonesgatifloxacin and moxifloxacin by CLSI serum standards.

S. aureus fluoroquinolone-susceptible MICs μg/ml Isolate Oligomer 4Oligomer 5  1—E402 0.25 0.5  2—E1512 0.25 0.25  3—E253 0.25 0.25 4—K1518 0.25 0.125  5—K1525 0.125 0.125  6—K1663 0.5 0.125  7—K16480.25 0.125  8—K1646 0.25 0.25  9—K1642 0.5 0.25 10—K1638 0.5 0.2511—K1628 0.25 0.25 12—K1618 0.5 0.125 13—K1617 0.25 0.25 14—K1611 0.250.25 15—K1607 0.25 0.25 16—K1600 0.25 0.125 17—K1591 0.25 0.5 18—K15850.25 0.25 19—K1583 0.25 0.25 20—K1574 0.25 0.25 21—K1566 0.25 0.2522—K1551 0.25 0.125 23—K1545 0.25 0.25 24—K1540 0.25 0.25 25—K1530 0.250.5 E. coli D31 1 (0.78)  16 (1.56) S. aureus ATCC 27660 2 (0.098) 16(0.78)MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

S. aureus fluoroquinolone-susceptible MIC₅₀ and MIC₉₀ Determinations andStatistics Oligomer 4 Oligomer 5 Row QSSA-A QSSA-A 1 0.125 0.125 2 0.2500.125 3 0.250 0.125 4 0.250 0.125 5 0.250 0.125 6 0.250 0.125 7 0.2500.125 8 0.250 0.250 9 0.250 0.250 10 0.250 0.250 11 0.250 0.250 12 0.2500.250 13 0.250 0.250 MIC₅₀ 14 0.250 0.250 15 0.250 0.250 16 0.250 0.25017 0.250 0.250 18 0.250 0.250 19 0.250 0.250 20 0.250 0.250 21 0.2500.250 22 0.500 0.250 MIC₉₀ 23 0.500 0.500 24 0.500 0.500 25 0.500 0.500

Descriptive Statistics

Variable N N* Mean SE Mean StDev Minimum Median Maximum Olig 4 QSSA 25 00.2850 0.0198 0.0990 0.1250 0.2500 0.5000 Olig 5 QSSA 25 0 0.2450 0.02220.1111 0.1250 0.2500 0.5000

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.25 μg/ml 0.25 μg/ml0.25 μg/ml 0.125-0.5 μg/ml Oligomer 5 0.25 μg/ml  0.5 μg/ml 0.25 μg/ml0.125-0.5 μg/ml

Mann-Whitney Test and CI: Oligomer 4 QSSA, Oligomer 5 QSSA

N Median Olig 4 QSSA 25 0.2500 Olig 5 QSSA 25 0.2500Point estimate for ETA1-ETA2 is 0.0000

95.2 Percent CI for ETA1-ETA2 is (−0.0000, 0.1250) W=712.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.1483The test is significant at 0.0731 NS (adjusted for ties)

S. aureus fluoroquinolone-resistant MICs μg/ml Isolate Oligomer 4Oligomer 5  1—E504 0.25 0.5  2—E475 0.25 0.25  3—E442 0.25 0.25  4—E4270.5 0.5  5—E425 0.25 0.25  6—E424 0.25 0.25  7—E417 1 0.25  8—E407 0.250.125  9—E401 0.25 0.25 10—K1659 0.25 0.25 11—E96 0.125 0.25 12—E379 0.50.5 13—E369 0.125 0.5 14—E361 0.25 0.25 15—E339 0.25 0.25 16—E333 0.250.125 17—E332 0.25 0.25 18—E327 0.5 0.25 19—E325 0.5 0.25 20—K950 0.50.25 21—K839 0.25 0.25 22—K1679 0.25 0.25 23—K1677 0.25 0.5 24—K16720.25 0.25 25—K1670 0.25 0.25 E. coli D31 1 (0.78)  4 (1.56) S. aureusATCC 27660 1 (0.098) 8 (0.78)MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

S. aureus fluoroquinolone-resistant MIC₅₀ and MIC₉₀ Determinations andStatistics Oligomer 4 Oligomer 5 Row QRSA-A QRSA-A 1 0.125 0.125 2 0.1250.125 3 0.250 0.250 4 0.250 0.250 5 0.250 0.250 6 0.250 0.250 7 0.2500.250 8 0.250 0.250 9 0.250 0.250 10 0.250 0.250 11 0.250 0.250 12 0.2500.250 13 0.250 0.250 MIC₅₀ 14 0.250 0.250 15 0.250 0.250 16 0.250 0.25017 0.250 0.250 18 0.250 0.250 19 0.250 0.250 20 0.500 0.250 21 0.5000.500 22 0.500 0.500 MIC₉₀ 23 0.500 0.500 24 0.500 0.500 25 1.000 0.500

Descriptive Statistics

Variable N N* Mean SE Mean StDev Minimum Median Maximum Olig 4 QRSA 25 00.3200 0.0361 0.1807 0.1250 0.2500 1.0000 Olig 5 QRSA 25 0 0.2900 0.02250.1125 0.1250 0.2500 0.5000

Summary of Results

MIC50 MIC90 Median MIC Range of MICs Oligomer 4 0.25 μg/ml 0.5 μg/ml0.25 μg/ml 0.125-1.0 μg/ml Oligomer 5 0.25 μg/ml 0.5 μg/ml 0.25 μg/ml0.125-0.5 μg/ml

Mann-Whitney Test and CI: Oligomer 4 QRSA, Oligomer 5 QRSA

N Median Olig 4 QRSA 25 0.2500 Olig 5 QRSA 25 0.2500Point estimate for ETA1-ETA2 is −0.0000

95.2 Percent CI for ETA1-ETA2 is (−0.0000, 0.0000) W=651.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.7934The test is significant at 0.7450 NS (adjusted for ties)

Control Bacteria

During the first sets of MICs performed with the S. aureusfluoroquinolone-susceptible and S. aureus fluoroquinolone-resistant, theMICs for the control bacteria (E. coli D31, and S. aureus ATC≡C 27660)for both Oligomer 4 and Oligomer 5 were much higher than those shownbelow.

Control for Control Isolate MIC Test Oligomer 4 Oligomer 5 E. coli D31SA-FQS 1 (0.78) 16 (1.56) S. aureus ATCC 27660 SA-FQS 2 (0.098) 16(0.78) E. coli D31 SA-FQR 1 (0.78) 4 (1.56) S. aureus ATCC 27660 SA-FQR1 (0.098) 8 (0.78)MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

A new set of MICs were performed with new batches of both Oligomer 4 andOligomer 5, and control bacteria, in quadruplicate. The results from theexperiment is as follows:

Control for Control Isolate MIC Test Oligomer 4 Oligomer 5 E. coli D31Control 1 (0.78) 8 (1.56) Only 1 S. aureus ATCC 27660 Control 0.25(0.098) 0.25 (0.78) Only 1 E. coli D31 Control 1 (0.78) 8 (1.56) Only 2S. aureus ATCC 27660 Control 0.25 (0.098) 0.25 (0.78) Only 2 E. coli D31Control 1 (0.78) 8 (1.56) Only 3 S. aureus ATCC 27660 Control 0.25(0.098) 0.5 (0.78) Only 3 E. coli D31 Control 1 (0.78) 16 (1.56) Only 4S. aureus ATCC 27660 Control 0.5 (0.098) 0.5 (0.78) Only 4MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

Although the MICs for Oligomer 5 for E. coli D31 remained high, the MICsfor S. aureus ATC≡C 27660 were for both Oligomer 4 and Oligomer 5 andOligomer 4 for E. coli D31 were within the acceptable range (1-2doubling dilutions) of the MICs previously obtained. It was decided tocontinue with the MIC determinations using the new batches of Oligomer 4and Oligomer 5 for all subsequent MIC determinations.

Since the MICs for both Oligomer 4 and Oligomer 5 with the S. aureusfluoroquinolone-susceptible and S. aureus fluoroquinolone-resistant weresimilar to that of the control S. aureus ATC≡C 27660 MIC performedpreviously, these MICs performed with the first batch of drugs would notbe repeated using the new batches of compounds.

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-susceptible MICs μg/ml Isolate Oligomer 4 Oligomer 5 1—E511 0.25 0.25  2—E489 0.125 0.125  3—E491 0.125 0.125  4—E476 0.250.25  5—E473 0.25 0.125  6—E462 0.125 0.125  7—E460 0.125 0.125  8—E4530.125 0.125  9—E448 0.125 0.125 10—E443 <0.0625 <0.0625 11—E441 <0.06250.125 12—E438 0.125 0.125 13—E437 0.125 0.125 14—E434 0.125 0.12515—E433 0.125 0.125 16—E430 <0.0625 0.125 17—E420 0.125 0.125 18—E4190.125 0.125 19—E403 0.125 0.125 20—E394 0.125 0.125 21—E393 0.125 0.12522—E328 0.25 0.25 23—E382 0.125 0.125 24—E381 0.125 0.25 25—E372 0.25<0.0625 E. coli D31   1 (0.78)   4 (1.56) S. aureus ATCC 0.25 (0.098)0.25 (0.78) 27660MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-susceptible MIC₅₀ and MIC₉₀ Determinations andStatistics For Statistical Calculation Purposes, <0.0625 was Replacedwith 0.03125. Oligomer 4 Oligomer 5 Row QSSE-A QSSE-A 1 0.03125 0.031252 0.03125 0.03125 3 0.03125 0.12500 4 0.12500 0.12500 5 0.12500 0.125006 0.12500 0.12500 7 0.12500 0.12500 8 0.12500 0.12500 9 0.12500 0.1250010 0.12500 0.12500 11 0.12500 0.12500 12 0.12500 0.12500 13 0.125000.12500 MIC₅₀ 14 0.12500 0.12500 15 0.12500 0.12500 16 0.12500 0.1250017 0.12500 0.12500 18 0.12500 0.12500 19 0.12500 0.12500 20 0.125000.12500 21 0.25000 0.12500 22 0.25000 0.25000 MIC₉₀ 23 0.25000 0.2500024 0.25000 0.25000 25 0.25000 0.25000

Descriptive Statistics

Variable N N* Mean SE Mean StDev Minimum Median Maximum Olig 4 QSSE 25 00.1388 0.0129 0.0645 0.0313 0.1250 0.2500 Olig 5 QSSE 25 0 0.1375 0.01130.0563 0.0313 0.1250 0.2500

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.125 μg/ml 0.25 μg/ml0.125 μg/ml 0.03125 - 0.25 μg/ml Oligomer 5 0.125 μg/ml 0.25 μg/ml 0.125μg/ml 0.03125 - 0.25 μg/ml

Mann-Whitney Test and CI: Oligomer 4 QSSE, Oligomer 5 QSSE

N Median Olig 4 QSSE 25 0.12500 Olig 5 QSSE 25 0.12500Point estimate for ETA1-ETA2 is 0.00000

95.2 Percent CI for ETA1-ETA2 is (−0.00002, 0.00000) W=638.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.9923

The test is significant at 0.9902 NS (adjusted for ties)

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant MICs μg/ml Isolate Oligomer 4 Oligomer 5 1—E515 0.125 0.125  2—E514 <0.0625 0.125  3—E513 0.125 0.125  4—E510<0.0625 0.125  5—E509 0.125 0.125  6—E508 0.125 0.125  7—E505 0.1250.125  8—E503 0.125 0.125  9—E502 0.125 0.25 10—E499 0.125 0.25 11—E4980.125 0.125 12—E494 <0.0625 0.125 13—E493 0.125 0.125 14—E485 0.1250.125 15—E487 0.125 <0.0625 16—E486 <0.0625 0.125 17—E480 0.125 0.12518—E475 0.25 0.125 19—E471 0.125 0.125 20—E458 0.125 0.125 21—E452 0.250.5 22—E450 0.125 0.125 23—E440 0.25 0.125 24—E446 0.125 <0.0625 25—E4440.25 0.25 E. coli D31   1 (0.78)   4 (1.56) S. aureus ATCC 0.25 (0.098)0.25 (0.78) 27660MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant MIC₅₀ and MIC₉₀ Determinations and StatisticsFor Statistical Calculation Purposes, <0.0625 was Replaced with 0.03125.Oligomer 4 Oligomer 5 Row QRSE-A QRSE-A 1 0.03125 0.03125 2 0.031250.03125 3 0.03125 0.12500 4 0.03125 0.12500 5 0.12500 0.12500 6 0.125000.12500 7 0.12500 0.12500 8 0.12500 0.12500 9 0.12500 0.12500 10 0.125000.12500 11 0.12500 0.12500 12 0.12500 0.12500 13 0.12500 0.12500 MIC₅₀14 0.12500 0.12500 15 0.12500 0.12500 16 0.12500 0.12500 17 0.125000.12500 18 0.12500 0.12500 19 0.12500 0.12500 20 0.12500 0.12500 210.12500 0.12500 22 0.25000 0.25000 MIC₉₀ 23 0.25000 0.25000 24 0.250000.25000 25 0.25000 0.50000

Descriptive Statistics

Variable N N* Mean SE Mean StDev Minimum Median Maximum Olig 4 QRSE 25 00.1300 0.0127 0.0636 0.0313 0.1250 0.2500 Olig 5 QRSE 25 0 0.1475 0.01790.0895 0.0313 0.1250 0.5000

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Olig- 0.125 μg/ml 0.25 μg/ml 0.125μg/ml 0.03125-0.25 μg/ml omer 4 Olig- 0.125 μg/ml 0.25 μg/ml 0.125 μg/ml 0.03125-0.5 μg/ml omer 5

Mann-Whitney Test and CI: Oligomer 4 QRSE, Oligomer 5 QRSE

N Median Olig 4 QRSE 25 0.12500 Olig 5 QRSE 25 0.12500Point estimate for ETA1-ETA2 is −0.00000

95.2 Percent CI for ETA1-ETA2 is (0.00001,−0.00002) W=614.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.6624The test is significant at 0.5800 NS (adjusted for ties)

Serratia marcescens MICs μg/ml Isolate Oligomer 4 Oligomer 5  1—K168132 >128  2—K1674 32 >128  3—K1558 4 >128  4—K1538 16 >128  5—K150332 >128  6—K1216 4 >128  7—K1496 8 >128  8—K1481 2 >128  9—K1470 32 >12810—K1468 2 >128 11—K1467 32 >128 12—K1462 16 >128 13—K1461 8 12814—K1413 16 >128 15—K1402 0.25 8 16—K1357 1 >128 17—K1351 0.5 6418—K1327 8 >128 19—K1321 8 >128 20—K1315 16 >128 21—K1306 8 >12822—K1290 8 >128 23—K1265 8 >128 24—K1263 8 >128 25—K1239 8 >128 E. coliD31 0.5 (0.78)   4 (1.56) S. aureus ATCC 0.25 (0.098) 0.5 (0.78) 27660MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

Serratia marcescens MIC₅₀ and MIC₉₀ Determinations and Statistics ForStatistical Calculation Purposes, >128 was Replaced with 256. Oligomer 4Oligomer 5 Row SM-A SM-A 1 0.25 8 2 0.50 64 3 1.00 128 4 2.00 256 5 2.00256 6 4.00 256 7 4.00 256 8 8.00 256 9 8.00 256 10 8.00 256 11 8.00 25612 8.00 256 13 8.00 256 MIC₅₀ 14 8.00 256 15 8.00 256 16 8.00 256 1716.00 256 18 16.00 256 19 16.00 256 20 16.00 256 21 32.00 256 22 32.00256 MIC₉₀ 23 32.00 256 24 32.00 256 25 32.00 256

Descriptive Statistics

Vari- SE Mini- Maxi- able N N* Mean Mean StDev mum Median mum Olig 4 250 12.39 2.21 11.04 0.25 8.00 32.00 SM Olig 5 25 0 233.3 13.0 65.1 8.0256.0 256.0 SM

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4  8 μg/ml  32 μg/ml  8μg/ml 0.25-32 μg/ml Oligomer 5 256 μg/ml 256 μg/ml 256 μg/ml   8-256μg/ml

Mann-Whitney Test and CI: Oligomer 4 SM, Oligomer 5 SM

N Median Olig 4 SM 25 8.00 Olig 5 SM 25 256.00Point estimate for ETA1-ETA2 is −248.00

95.2 Percent CI for ETA1-ETA2 is (−247.98,−239.99) W=338.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0000The test is significant at 0.0000 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent)

Pseudomonas aeruginosa MICs μg/ml Isolate Oligomer 4 Oligomer 5  1—K16732 32  2—K1668 2 64  3—K1662 2 64  4—K1657 2 64  5—K1651 4 128  6—K1649 464  7—K1564 8 >128  8—K1636 0.5 4.0  9—K1634 2 128 10—K1633 4 6411—K1632 4 64 12—K1631 8 64 13—K1629 4 64 14—K1627 2 64 15—K1626 8 12816—K1625 4 64 17—K1562 4 128 18—K1613 4 32 19—K1553 2 128 20—K1594 2 6421—K1588 4 128 22—K1554 4 128 23—K1580 2 32 24—K1577 2 64 25—K1576 4 128E. coli D31 0.5 (0.78)    8 (1.56) S. aureus ATCC 0.5 (0.098) 0.25(0.78) 27660MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.

Pseudomonas aeruginosa MIC₅₀ and MIC₉₀ Determinations and Statistics ForStatistical Calculation Purposes, >128 was Replaced with 256. Oligomer 4Oligomer 5 Row PA-A PA-A 1 0.5 4 2 2.0 32 3 2.0 32 4 2.0 32 5 2.0 64 62.0 64 7 2.0 64 8 2.0 64 9 2.0 64 10 2.0 64 11 2.0 64 12 4.0 64 13 4.064 MIC₅₀ 14 4.0 64 15 4.0 64 16 4.0 64 17 4.0 128 18 4.0 128 19 4.0 12820 4.0 128 21 4.0 128 22 4.0 128 MIC₀  23 8.0 128 24 8.0 128 25 8.0 256

Descriptive Statistics

Vari- Mini- Maxi- able N N* Mean SE Mean StDev mum Median mum Olig 25 03.540 0.398 1.989 0.500 4.000 8.000 4 PA Olig 25 0 85.9 10.4 51.8 4.064.0 256.0 5 PA

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4  4 μg/ml  4 μg/ml  4μg/ml  0.5-8 μg/ml Oligomer 5 64 μg/ml 128 μg/ml 64 μg/ml 4-256 μg/ml

Mann-Whitney Test and CI: Oligomer 4 PA, Oligomer 5 PA

N Median Olig 4 PA 25 4.00 Olig 5 PA 25 64.00Point estimate for ETA1-ETA2 is −62.00

95.2 Percent CI for ETA1-ETA2 is (−120.00,−60.00) W=333.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0000The test is significant at 0.0000 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent)

Streptococcus pneumoniae MICs μg/ml Isolate Oligomer 4 Oligomer 5 1—B1386 >64 >64  2—B1380 1 4  3—B1378 1 0.5  4—B1377 2 8  5—B1373 1 8 6—B1367 1 16  7—B1355 2 8  8—B1353 1 4  9—B1351 1 1 10—B1339 1 211—B1337 0.5 1 12—B1335 2 1 13—B1334 1 1 14—B1333 1 1 15—B1255 0.5 116—B1288 1 8 17—B1287 1 16 18—B1272 0.5 1 19—B1264 0.5 1 20—B1252 1 1621—B1245 0.5 2 22—B1211 1 8 23—B1213 1 16 24—B1208 0.5 8 25—B1214 1 4 E.coli D31* 2 2 S. aureus ATCC 1 1 27660* E. coli D31** 0.5 (0.78) 16(1.56) S. aureus ATCC 0.25 (0.098)  2 (0.78) 27660** *Control BacteriaSet #1; **Control Bacteria Set #2; (MICs for Control Bacteria (E. coli,S. aureus) are within the parentheses.)

Streptococcus pneumoniae MIC₅₀ and MIC₉₀ Determinations and StatisticsFor Statistical Calculation Purposes, >64 was Replaced with 128.Oligomer 4 Oligomer 5 Row SP-A SP-A 1 0.5 0.5 2 0.5 1.0 3 0.5 1.0 4 0.51.0 5 0.5 1.0 6 0.5 1.0 7 1.0 1.0 8 1.0 1.0 9 1.0 1.0 10 1.0 2.0 11 1.02.0 12 1.0 4.0 13 1.0 4.0 MIC₅₀ 14 1.0 4.0 15 1.0 8.0 16 1.0 8.0 17 1.08.0 18 1.0 8.0 19 1.0 8.0 20 1.0 8.0 21 1.0 16.0 22 2.0 16.0 MIC₉₀ 232.0 16.0 24 2.0 16.0 25 128.0 128.0

Descriptive Statistics

Var- Mini- Maxi- iable N N* Mean SE Mean StDev mum Median mum Olig 4 SP25 0 6.08 5.08 25.40 0.50 1.00 128.00 Olig 5 SP 25 0 10.58 5.01 25.050.50 4.00 128.00

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 1 μg/ml  2 μg/ml 1 μg/ml0.5-128 μg/ml Oligomer 5 4 μg/ml 16 μg/ml 4 μg/ml   4-128 μg/ml

Mann-Whitney Test and CI: Oligomer 4 SP, Oligomer 5 SP

N Median Olig 4 SP 25 1.000 Olig 5 SP 25 4.000Point estimate for ETA1-ETA2 is −3.000

95.2 Percent CI for ETA1-ETA2 is (−6.999,−0.499) W=457.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0005

The test is significant at 0.0002 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent)

Streptococcus viridans group MICs μg/ml Isolate Oligomer 4 Oligomer 5 1—K1684 2 8  2—K1680 4 64  3—E546 1 8  4—E272 2 16  5—E506 16 >64 6—E496 1 0.5  7—E456 4 16  8—E432 4 8  9—E423 4 >64 10—E418 8 >6411—E412 2 8 12—E409 8 32 13—E405 4 >64 14—E404 32 >64 15—E396 16 3216—E262 1 4 17—E362 4 16 18—E359 4 32 19—E348 8 16 20—E344 4 4 21—E308 44 22—E294 4 2 23—E292 4 0.5 24—E285 4 0.5 25—E265 1 8 E. coli D31* 2 2S. aureus ATCC 2 1 27660* E. coli D31** 0.5 (0.78) 16 (1.56) S. aureusATCC   1 (0.098)  1 (0.78) 27660** *Control Bacteria Set #1; **ControlBacteria Set #2; (MICs for Control Bacteria (E. coli, S. aureus) arewithin the parentheses.)

Streptococcus viridans group MIC₅₀ and MIC₉₀ Determinations andStatistics For Statistical Calculation Purposes, >64 was Replaced with128. Oligomer 4 Oligomer 5 Row SV-A SV-A 1 1 0.5 2 1 0.5 3 1 0.5 4 1 2.05 2 4.0 6 2 4.0 7 2 4.0 8 4 8.0 9 4 8.0 10 4 8.0 11 4 8.0 12 4 8.0 13 416.0 MIC₅₀ 14 4 16.0 15 4 16.0 16 4 16.0 17 4 32.0 18 4 32.0 19 4 32.020 8 64.0 21 8 128.0 22 8 128.0 MIC₉₀ 23 16 128.0 24 16 128.0 25 32128.0

Descriptive Statistics

SE Mini- Variable N N* Mean Mean StDev mum Median Maximum Olig 4 SV 25 05.84 1.34 6.72 1.00 4.00 32.00 Olig 5 SV 25 0 36.78 9.72 48.59 0.5016.00 128.00

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4  4 μg/ml  8 μg/ml  4μg/ml   1-32 μg/ml Oligomer 5 16 μg/ml 128 μg/ml 16 μg/ml 0.5-128 μg/ml

Mann-Whitney Test and CI: Oligomer 4 SV, Oligomer 5 SV

N Median Olig 4 SV 25 4.00 Olig 5 SV 25 16.00Point estimate for ETA1-ETA2 is −7.00

95.2 Percent CI for ETA1-ETA2 is (−23.99,−3.01) W=487.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0037The test is significant at 0.0031 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent)

Moraxella species & Moraxella catarrhalis Combined MS = Moraxellaspecies; MC = Moraxella (Branhamella) catarrhalis Isolate Oligomer 4Oligomer 5  1—K1614 - MS 16 64  2—K1661 - MS 32 16  3—K1643 - MS 640.125  4—K1640 - MS 8.0 8.0  5—B1431 - MS 32 0.5  6—B1429 - MS 1 1 7—B1418 - MS 32 0.25  8—K1784 - MS 64 0.25  9—K1773 - MS 64 0.2510—K1369 - MS 2.0 2.0 11—B1275 - MS 2.0 0.125 12—B1221 - MS 2.0 0.12513—B1172 - MS >64 >64 14—E542 - MS 2.0 2.0 15—K678 - MS 2.0 0.516—K660 - MS 2.0 0.25 17—K599 - MC 0.5 0.25 18—K1650 - MC 64 0.2519—K1373 - MC 1.0 0.125 20—K1553 - MC 4.0 2.0 21—K1453 - MC 4.0 6422—K1227 - MC 2.0 1.0 23—B1102 - MC 1.0 0.5 24—K1819 - MC 4.0 3225—K1855 - MC 2.0 8.0 E. coli D31* 4 2 S. aureus ATCC 1 1 27660* E. coliD31**  1 (0.78)  16 (1.56) S. aureus ATCC 0.5 (0.098) 0.5 (0.78) 27660***Control Bacteria Set #1; **Control Bacteria Set #2; (MICs for ControlBacteria (E. coli, S. aureus) are within the parentheses.)

Moraxella species & Moraxella catarrhalis Combined MIC₅₀ and MIC₉₀Determinations and Statistics For Statistical Calculation Purposes, >64was Replaced with 128. Oligomer 4 Oligomer 5 Row MS-A MS-A 1 0.5 0.125 21.0 0.125 3 1.0 0.125 4 1.0 0.125 5 2.0 0.250 6 2.0 0.250 7 2.0 0.250 82.0 0.250 9 2.0 0.250 10 2.0 0.250 11 2.0 0.500 12 2.0 0.500 13 4.00.500 MIC₅₀ 14 4.0 1.000 15 4.0 1.000 16 8.0 2.000 17 16.0 2.000 18 32.02.000 19 32.0 8.000 20 32.0 8.000 21 64.0 16.000 22 64.0 32.000 MIC₉₀ 2364.0 64.000 24 64.0 64.000 25 128.0 128.000

Descriptive Statistics

SE Mini- Variable N N* Mean Mean StDev mum Median Maximum Olig 4 MS 25 021.42 6.43 32.13 0.50 4.00 128.00 Olig 5 MS 25 0 13.26 6.00 30.00 0.130.50 128.00

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 4 μg/ml 64 μg/ml 4 μg/ml0.5-128 μg/ml Oligomer 5 0.5 μg/ml 32 μg/ml 0.5 μg/ml 0.125-128 μg/ml

Mann-Whitney Test and CI: Oligomer 4 MS, Oligomer 5 MS

N Median Olig 4 MS 25 4.00 Olig 5 MS 25 0.50Point estimate for ETA1-ETA2 is 1.75

95.2 Percent CI for ETA1-ETA2 is (0.75, 6.00) W=785.0

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0043The test is significant at 0.0040 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent)

Haemophilus influenzae MICs μg/ml Isolate Oligomer 4 Oligomer 5  1—B13598 >64  2—B1346 8 >64  3—B1345 8 >64  4—B1343 8 >64  5—B1338 4 16 6—B1332 8 64  7—B1331 8 >64  8—B1330 8 >64  9—B1379 16 8 10—B1378 8 411—B1313 4 2 12—B1477 8 4 13—B1286 8 2 14—B1282 32 8 15—B1291 8 1616—B1280 8 16 17—B1279 16 64 18—B1260 8 16 19—B1238 2 8 20—B1209 4 821—B1249 4 16 22—B1248 8 4 23—B1244 8 32 24—B1419 4 32 25—B1222 8 >64 E.coli D31 8 16 S. aureus ATCC 27660 4 4 E. coli D31 1 (0.78) 16 (1.56) S.aureus ATCC 27660 0.5 (0.098) 0.5 (0.78) * Control Bacteria Set #1; **Control Bacteria Set #2; (MICs for Control Bacteria (E. coli, S. aureus)are within the parentheses.)

Haemophilus influenzae MIC₅₀ and MIC₉₀ Determinations and Statistics ForStatistical Calculation Purposes, >64 was Replaced with 128. Oligomer 4Oligomer 5 Row HI-A HI-A 1 2 2 2 4 2 3 4 4 4 4 4 5 4 4 6 4 8 7 8 8 8 8 89 8 8 10 8 16 11 8 16 12 8 16 13 8 16 MIC₅₀ 14 8 16 15 8 32 16 8 32 17 864 18 8 64 19 8 128 20 8 128 21 8 128 22 8 128 MIC₅₀ 23 16 128 24 16 12825 32 128

Descriptive Statistics

SE Mini- Variable N N* Mean Mean StDev mum Median Maximum Olig 4 HI 25 08.56 1.16 5.82 2.00 8.00 32.00 Olig 5 HI 25 0 48.6 10.6 53.0 2.0 16.0128.0

Summary of Results

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 8 μg/ml 8 μg/ml 8 μg/ml2-32 μg/ml Oligomer 5 16 μg/ml 128 μg/ml 16 μg/ml 2-128 μg/ml

Mann-Whitney Test and CI: Oligomer 4 HI, Oligomer 5 HI

N Median Olig 4 HI 25 8.00 Olig 5 HI 25 16.00

Point estimate for ETA1-ETA2 is −8.00

95.2 Percent CI for ETA1-ETA2 is (−56.00, 0.00) W=493.5

Test of ETA1=ETA2 vs ETA1 not=ETA2 is significant at 0.0054The test is significant at 0.0038 (adjusted for ties)

Oligomer 4>Oligomer 5 (More Potent>Less Potent) Summary of Results

MIC Determinations of Control Bacteria from Each Day of MIC Testing MICs[μg/ml] Control for Control Isolate MIC Test Oligomer 4 Oligomer 5 E.coli D31 SA-FQS 1 (0.78) 16 (1.56) S. aureus ATCC 27660 SA-FQS 2 (0.098)16 (0.78) E. coli D31 SA-FQR 1 (0.78) 4 (1.56) S. aureus ATCC 27660SA-FQR 1 (0.098) 8 (0.78) E. coli D31 Control 1 (0.78) 8 (1.56) Only 1S. aureus ATCC 27660 Control 0.25 (0.098) 0.25 (0.78) Only 1 E. coli D31Control 1 (0.78) 8 (1.56) Only 2 S. aureus ATCC 27660 Control 0.25(0.098) 0.25 (0.78) Only 2 E. coli D31 Control 1 (0.78) 8 (1.56) Only 3S. aureus ATCC 27660 Control 0.25 (0.098) 0.5 (0.78) Only 3 E. coli D31Control 1 (0.78) 16 (1.56) Only 4 S. aureus ATCC 27660 Control 0.5(0.098) 0.5 (0.78) Only 4 E. coli D31 SE-FQS 1 (0.78) 4 (1.56) S. aureusATCC 27660 SE-FQS 0.25 (0.098) 0.25 (0.78) E. coli D31 SE-FQR 1 (0.78) 4(1.56) S. aureus ATCC 27660 SE-FQR 0.25 (0.098) 0.25 (0.78) E. coli D31SM 0.5 (0.78) 4 (1.56) S. aureus ATCC 27660 SM 0.25 (0.098) 0.5 (0.78)E. coli D31 PA 0.5 (0.78) 8 (1.56) S. aureus ATCC 27660 PA 0.5 (0.098)0.25 (0.78) E. coli D31 SP 0.5 (0.78) 16 (1.56) S. aureus ATCC 27660 SP0.25 (0.098) 2 (0.78) E. coli D31 SV 0.5 (0.78) 16 (1.56) S. aureus ATCC27660 SV 1 (0.098) 1 (0.78) E. coli D31 MS 1 (0.78) 16 (1.56) S. aureusATCC 27660 MS 0.5 (0.098) 0.5 (0.78) E. coli D31 HI 1 (0.78) 16 (1.56)S. aureus ATCC 27660 HI 0.5 (0.098) 0.5 (0.78)MICs for Control Bacteria (E. coli, S. aureus) are within theparentheses.Summary of MIC Results (n=25 per group)

S. aureus fluoroquinolone-susceptible

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.25 μg/ml 0.25 μg/ml0.25 μg/ml 0.125-0.5 μg/ml Oligomer 5 0.25 μg/ml 0.5 μg/ml 0.25 μg/ml0.125-0.5 μg/ml

S. aureus fluoroquinolone-resistant

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.25 μg/ml 0.5 μg/ml0.25 μg/ml 0.125-1.0 μg/ml Oligomer 5 0.25 μg/ml 0.5 μg/ml 0.25 μg/ml0.125-0.5 μg/ml

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)FQ-susceptible

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.125 μg/ml 0.25 μg/ml0.125 μg/ml 0.03125-0.25 μg/ml Oligomer 5 0.125 μg/ml 0.25 μg/ml 0.125μg/ml 0.03125-0.25 μg/ml

Staphylococcus epidermidis (Coagulase-negative Staphylococcus)FQ-resistant

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 0.125 μg/ml 0.25 μg/ml0.125 μg/ml 0.03125-0.25 μg/ml Oligomer 5 0.125 μg/ml 0.25 μg/ml 0.125μg/ml 0.03125-0.5 μg/ml

Serratia marcescens

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 8 μg/ml 32 μg/ml 8 μg/ml0.25-32 μg/ml Oligomer 5 256 μg/ml 256 μg/ml 256 μg/ml 8-256 μg/ml

Pseudomonas aeruginosa

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 4 μg/ml 4 μg/ml 4 μg/ml0.5-8 μg/ml Oligomer 5 64 μg/ml 128 μg/ml 64 μg/ml 4-256 μg/ml

Streptococcus pneumoniae

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 1 μg/ml 2 μg/ml 1 μg/ml0.5-128 μg/ml Oligomer 5 4 μg/ml 16 μg/ml 4 μg/ml 4-128 μg/ml

Streptococcus viridans group

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 4 μg/ml 8 μg/ml 4 μg/ml1-32 μg/ml Oligomer 5 16 μg/ml 128 μg/ml 16 μg/ml 0.5-128 μg/ml

Moraxella species (Including Moraxella catarrhalis)

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 4 μg/ml 64 μg/ml 4 μg/ml0.5-128 μg/ml Oligomer 5 0.5 μg/ml 32 μg/ml 0.5 μg/ml 0.125-128 μg/ml

Haemophilus influenzae

MIC₅₀ MIC₉₀ Median MIC Range of MICs Oligomer 4 8 μg/ml 8 μg/ml 8 μg/ml2-32 μg/ml Oligomer 5 16 μg/ml 128 μg/ml 16 μg/ml 2-128 μg/ml

Oligomer 4 and Oligomer 5 demonstrated the lowest MICs forStaphylococcus aureus fluoroquinolone-susceptible, Staphylococcus aureusfluoroquinolone-resistant, Staphylococcus epidermidis(Coagulase-negative Staphylococcus) fluoroquinolone-susceptible,Staphylococcus epidermidis (Coagulase-negative Staphylococcus)fluoroquinolone-resistant. Median MIC determinations were less than orequal to 0.25 μg/ml for the compounds against the ocular isolates ofthese species. The median MICs for Oligomer 4 and Oligomer 5 againstStreptococcus pneumoniae and Moraxella species (including Moraxellacatarrhalis) were less than or equal to 4 μg/ml. The median MIC forOligomer 4 against Streptococcus viridans group was 4 μg/ml whereas themedian MIC for Oligomer 5 was 16 μg/ml. Oligomer 4 and Oligomer 5demonstrated the highest MICs against the Gram-negative pathogensSerratia marcescens, Pseudomonas aeruginosa, and Haemophilus influenzae.The median MIC of Oligomer 4 to Pseudomonas aeruginosa, Serratiamarcescens and Haemophilus influenzae were 4, 8, and 8 μg/mlrespectively The median MICs of Oligomer 5 to Pseudomonas aeruginosa,Serratia marcescens and Haemophilus influenzae were 64, 128, and 16μg/ml respectively. Overall, MICs for the Control Bacteria (E. coli D31and S. aureus ATC≡C 27660) for each date on which MICs were performedwere within the acceptable standard of a 1-2 dilution range in MICs fromthe MICs previously obtained for those compounds and between differentpreparation days. The addition of 2% lysed horse red blood cells to theMueller-Hinton broth for MIC testing with Streptococcus pneumoniae,Moraxella species (including Moraxella catarrhalis), and Streptococcusviridans group appeared to decrease the activity of the Oligomer 4against the Control Bacteria (E. coli D31 and S. aureus ATC≡C 27660)approximately 4 fold. It is unknown whether the 2% lysed horse red bloodcells had the same effect on the test isolates. The addition of 2% lysedhorse red blood cells to the Mueller-Hinton broth for MIC testing withStreptococcus pneumoniae, Moraxella species (including Moraxellacatarrhalis), and Streptococcus viridans group generally appeared toincrease or have no effect on the activity of the Oligomer 5 against theControl Bacteria (E. coli D31 and S. aureus ATC≡C 27660). It is unknownwhether the 2% lysed horse red blood cells had the same effect on thetest isolates. The use of HTM broth for the MIC testing of Haemophilusinfluenzae appeared to decrease the activity of the Oligomer 4 andOligomer 5 against the Control Bacteria S. aureus ATC≡C 27660approximately 8 fold. The use of HTM broth for the MIC testing ofHaemophilus influenzae appeared to decrease the activity of the Oligomer4 against the Control Bacteria E. coli D31 approximately 8 fold butappeared to have no effect on the activity of Oligomer 5 against theControl Bacteria E. coli D31.

Oligomer 4 and Oligomer 5 demonstrated the lowest MICs against a varietyof Gram-positive ocular bacterial isolates and at least oneGram-negative ocular bacterial species (Moraxella). Oligomer 4 andOligomer 5 demonstrated varying in vitro antibacterial activity againstthe three species that are the leading causes of conjunctivitis(Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilusinfluenzae). The order of the lower MICs for Oligomer 4 and Oligomer 5against the species was: Staphylococcus aureus<Streptococcuspneumoniae<Haemophilus influenzae. (<=lower MICs). Oligomer 4demonstrated lower MICs than Oligomer 5 for all bacterial species testedexcept for the Staphylococcal species (equipotent) and for Moraxellaspecies (less potent).

Example 9 Ker-1

One purpose of the following experiments was to compare the efficacy of1% Oligomer 2, 0.5% Oligomer 2, and 5% vancomycin in the treatment of afluoroquinolone-resistant, methicillin-resistant Staphylococcus aureusinfection in the NZW rabbit keratitis model with or without intactcorneal epithelia.

Fifteen rabbits were received from Myrtles' Rabbitry, Thompson Station,TN. The clinical isolate of fluoroquinolone-resistant,methicillin-resistant (MRSA) Staphylococcus aureus (K₉₅₀) wassubcultured on 5% sheep blood agar and incubated at 37° C. in 6% CO₂overnight. The next morning, the MRSA strain was suspended in steriletrypticase soy broth to a 0.5 McFarland Standard, containingapproximately 5×10⁸ cfu/ml of bacteria. The absorbance of the suspensionwas measured at 650 nm using a Beckman DU-70 spectrophotometer. ODreadings of 0.07 corresponded to 5×10⁸ cfu/ml of bacteria. Thisconcentration was appropriately diluted in sterile trypticase soy brothto provide the inoculum of approximately 1,000 (1.0×10³) cfu/eye in 25μl. Colony counts were performed on the inoculum to determine the actualcfu inoculated. Following general anesthesia with ketamine and xylazineand topical anesthesia with proparacaine and prior to bacterialinoculation in the left eyes, 6 mm areas of the corneal epithelia wasremoved centrally with an Amoils epithelial scrubber. Nothing was doneto the right eyes. The 15 rabbits were then inoculated intrastromally inboth eyes with 25 μl of the bacterial dilution of approximately 10³cfu/eye of the bacteria. The bacterial inoculation of the left eyes wasdirectly under the epithelial defect created by the Amoils epithelialscrubber. The epithelia were removed in the left corneas in order todetermine whether this layer of the cornea is a barrier for Oligomer 2penetration when compared to the right cornea with an intact epithelium.A colony count was done on the inoculum to determine the actual cfuinoculated. The rabbits were immediately treated with analgesia in theform of and intramuscular injection of ketoprofen, 1.5 mg/kg. After 4hours, the 15 rabbits were divided into 4 treatment groups and oneuntreated control group sacrificed at the onset of therapy. Both eyes ofeach rabbit of the treatment groups were treated with one 37 μl drop ofthe coded solutions or control Saline or 1 drop of vancomycin from itsdropper bottle. The Oligomer 2 concentrations were masked and labeled as1 and 2. The masked concentrations were 1% Oligomer 2 and 0.5% Oligomer2 but the specific concentrations of solutions were not known to the labworkers who carried out the experiment. The vancomycin and control(Tris-Buffered Saline) were not masked.

Groups:

Left Right Rx—Both Treatment Rabbit Group Eye Eye Eyes Regimen # IAbraded Intact Oligomer 2 Every 15 minutes 1-3 Epithe- Epithe- (PMX-1)for 5 hours (21 lium lium total doses) II Abraded Intact Oligomer 2Every 15 minutes 4-6 Epithe- Epithe- (PMX-2) for 5 hours (21 lium liumtotal doses) III Abraded Intact Vancomycin Every 15 minutes 7-9 Epithe-Epithe- (50 mg/ml) for 5 hours (21 lium lium (Van) total doses) IVAbraded Intact Tris- Every 15 minutes 10-12 Epithe- Epithe- Buffered for5 hours (21 lium lium Saline total doses) (Con) V Abraded IntactSacrifice None 13-15 Epithe- Epithe- at Onset of lium lium Therapy (4hours PI) (ONSET)

Treatment was scheduled for every 15 minutes for 5 hours (21 totaldoses). However, PMX-1 and PMX-2 were exhausted after the 19^(th) dose.Therefore, the actual treatment was 15 minutes for 4.5 hours (19 totaldoses). The 3 rabbits in group V were sacrificed 4 hours PI and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were done on the homogenates using 5% sheep blood agarplates to determine the amount of bacteria contained in the corneas atthe onset of therapy. Following the completion of therapy, the eyes wereexamined for clinical signs of infection. One hour after the finaltreatment, the treated rabbits (Groups I-IV) were sacrificed and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were performed on the homogenates using 5% sheep bloodagar plates to determine the amount of bacteria contained in the corneasafter treatment. The next morning, the plates were counted and thenumber of cfu/eye of Staphylococcus aureus was determined for eachcornea.

Formulations: 1) Oligomer 2 (PMX-1): Oligomer 2 powder, on the day oftreatment, was dissolved in 5 ml of Tris-Buffered Saline (TBS) beforeuse. The solution was stored at room temperature during the 5 hours ofuse. 37 μl drops were instilled using a Rainin EDP electronic pipet setin the multi-dispense mode. This solution was designated PMX-1. 2)Oligomer 2 (PMX-2): Oligomer 2 powder, on the day of treatment, wasdissolved in 5 ml of Tris-Buffered Saline (TBS) before use. The solutionwas stored at room temperature during the 5 hours of use. 37 μl dropswere instilled using a Rainin EDP electronic pipet set in themulti-dispense mode. This solution was designated PMX-2. 3) 5%Vancomycin (50 mg/ml): Vancomycin (50 mg/ml) eye drops was purchasedfrom the UPMC pharmacy as the fortified preparation used in patients.Vancomycin was administered using is supplied dropper bottle. 4) Control(Tris-Buffered Saline): 37 μl drops were instilled using a Rainin EDPelectronic pipet set in the multi-dispense mode.

IACUC Protocol #0701145 “The In Vivo Evaluation of Biomimetics asTopical Ocular Antibiotics”.

MIC Characterization of Fluoroquinolone-Resistant Methicillin- ResistantStaphylococcus aureus Strain K950 Antibiotic MIC [μg/ml] (MinimumInhibitory Concentration) Oligomer 2 0.25 μg/ml Vancomycin 2 μg/ml DropSchedule Drop # Time Time of Day 1 0    9:30 2  :15  9:45 3  :30 10:00 4 :45 10:15 5 1:00 10:30 6 1:15 10:45 7 1:30 11:00 8 1:45 11:15 9 2:0011:30 10 2:15 11:45 11 2:30 12:00 12 2:45 12:15 13 3:00 12:30 14 3:1512:45 15 3:30  1:00 16 3:45  1:15 17 4:00  1:30 18 4:15  1:45 19 4:30  2:00** **Drops were stopped after Drop 19 because all of the PMX-1 andPMX-2 solutions were used at that time. Sacrifice rabbits 1 hour afterfinal drop (3:00).

DEFINITIONS OF ABBREVIATIONS

PMX-1-IE Oligomer 2 with Intact EpitheliumPMX-1-AE Oligomer 2 with Abraded EpitheliumPMX-2-IE Oligomer 2 with Intact EpitheliumPMX-2-AE Oligomer 2 with Abraded EpitheliumVAN-IE 5% Vancomycin with Intact EpitheliumVAN-AE 5% Vancomycin with Abraded EpitheliumCON-AE Tris-Buffered Saline Control with Abraded EpitheliumCON-IE Tris-Buffered Saline Control with Intact Epithelium

Clinical Evaluation—Results

Corneal Corneal Total Eye Group Conj. Chemosis Discharge Iritis EdemaInfiltrate Score 1R PMX-1-IE 2.5 2.5 3.0 1.5 2.0 2.5 14.0 2R PMX-1-IE3.0 3.0 2.5 0.5 1.0 2.5 12.5 3R PMX-1-IE 3.0 3.0 3.0 0.5 1.5 2.5 14.5 1LPMX-1-AE 2.5 2.5 3.0 1.5 2.5 1.0 13.0 2L PMX-1-AE 3.0 3.0 3.0 0.5 1.0 010.5 3L PMX-1-AE 2.0 2.0 3.0 0.5 1 0.5 9.0 4R PMX-2-IE 3.0 3.0 3.0 2.02.5 2.0 15.5 5R PMX-2-IE 3.0 3.0 3.0 2.0 2.0 2.5 15.5 6R PMX-2-IE 3.03.0 3.0 0.5 2.0 2.0 13.5 4L PMX-2-AE 3.0 3.0 3.0 2.0 1.0 0 12.0 5LPMX-2-AE 3.0 3.0 2.5 1.0 2.0 0 11.5 6L PMX-2-AE 3.0 3.0 2.5 1.0 1.0 010.5 7R VAN-IE 2.5 3.0 3.0 2.0 1.0 0 11.5 8R VAN-IE 3.0 3.0 3.0 2.0 1.00 12.0 9R VAN-IE 3.0 3.0 2.5 1.0 1.0 0.5 11.0 7L VAN-AE 3.0 3.0 3.0 1.00.5 0.5 11.0 8L VAN-AE 2.5 2.5 2.0 1.5 1.0 0 9.5 9L VAN-AE 2.5 2.5 2.51.5 1.0 0 10.0 10R  CON-IE 1.5 2.0 0.5 1.0 1.0 2.5 8.5 11R  CON-IE 1.0 00 0.5 2.0 2.5 6.0 12R  CON-IE 0 0 0 1.5 1.0 2.5 5.0 10L  CON-AE 1.5 2.01.0 1.5 1.0 0.5 7.5 11L  CON-AE 1.5 2.0 0.5 0.5 0 0.5 5.0 12L  CON-AE0.5 0.5 1.0 1.0 1.5 2.0 6.5 Scale 0 = Normal; 0.5 = Trace; 1.0 = Mild;1.5 = Mild/Moderate; 2.0 = Moderate; 2.5 = Moderate/Severe; 3.0 = Severe

Clinical Evaluation—Statistics

Descriptive Statistics Total Ocular Score Variable N Mean Median TrMeanStDev SE Mean PMX-1-IE Score 3 13.667 14.000 13.667 1.041 0.601 PMX-1-AEScore 3 10.83 10.50 10.83 2.02 1.17 PMX-2-IE Score 3 14.833 15.50014.833 1.155 0.667 PMX-2-AE Score 3 11.333 11.500 11.333 0.764 0.441VAN-IE Score 3 11.500 11.500 11.500 0.500 0.289 VAN-AE Score 3 10.16710.000 10.167 0.764 0.441 CON-IE Score 3 6.50 6.00 6.50 1.80 1.04 CON-AEScore 3 6.333 6.500 6.333 1.258 0.726 Duncan Multiple Comparisons TestTotal Score Row # Group/Level Mean Rank C.I. Overlaps 1 CON-IE Sco3.5000 2, 2 CON-AE Sco 3.5000 1, 3 VAN-AE Sco 9.8333 4, 5, 6, 4 PMX-1-AES 12.1667 3, 5, 6, P = 0.05 5 PMX-2-AE S 13.8333 3, 4, 6, 6 VAN-IE Sco14.5000 3, 4, 5, 7 PMX-1-IE S 20.3333 8, 8 PMX-2-IE S 22.3333 7, CON IE= CON AE < VAN AE = PMX-1AE = PMX-2AE = VAN IE < PMX-1 IE = PMX-2 IE

Microbiological Results

Inoculum = 1048 cfu/cornea Data Display CFU/ml Row PMX-1-IE PMX-1-AEPMX-2-IE PMX-2-AE 1 1700000 35 130000 5 2 16400 2380 1550000 100 310300000 750 15600000 0 VAN- Onset- Row IE VAN-AE CON-IE CON-AE Onset-IEAE 1 550 200 16000000 1200000 90000000 79500 2 450 700 3550000 85000140000 32000 3 600 750 8700000 7500000 98000 110000 Log₁₀ CFU/mlPMX-2-AE Row PMX-1-IE Log PMX-1-AE Log PMX-2-IE Log Log 1 6.230451.54407 5.11394 0.69897 2 4.21484 3.37658 6.19033 2.00000 3 7.012842.87506 7.19312 0.00000 Row VAN-IE Log VAN-AE Log CON-IE Log CON-AE Log1 2.74036 2.30103 7.20412 6.07918 2 2.65321 2.84510 6.55023 4.92942 32.77815 2.87506 6.93952 6.87506 Row Onset-IE Log Onset-AE Log 1 7.954244.90037 2 5.14613 4.50515 3 4.99123 5.04139 Descriptive Statistics Log₁₀CFU/ml Variable N Mean Median TrMean StDev SE Mean PMX-1-IE 3 5.8196.230 5.819 1.444 0.833 PMX-1-AE 3 2.599 2.875 2.599 0.947 0.547PMX-2-IE 3 6.166 6.190 6.166 1.040 0.600 PMX-2-AE 3 0.900 0.699 0.9001.015 0.586 VAN-IE Log 3 2.7239 2.7404 2.7239 0.0641 0.0370 VAN-AE Log 32.674 2.845 2.674 0.323 0.187 CON-IE Log 3 6.898 6.940 6.898 0.329 0.190CON-AE Log 3 5.961 6.079 5.961 0.978 0.565 Onset-IE Log 3 6.031 5.1466.031 1.668 0.963 Onset-AE Log 3 4.816 4.900 4.816 0.278 0.160

Microbiological Results—Intact Epithelium

Microbiological Results—Intact Epithelium

Power and Sample Size One-way ANOVA Sigma = 1.101 Alpha = 0.05 Number ofLevels = 5 Corrected Sum of Squares of Means = 10.4840 Means = 6.898,6.031, 5.819, 6.166, 2.724 Sample Size Power 3 0.9137 Duncan MultipleComparisons Test Log₁₀ CFU/ml Row # Group/Level Mean Rank C.I. Overlaps1 VAN-IE Log 2.0000 2 PMX-1-IE L 8.3333 3, 4, 5, 3 PMX-2-IE L 9.0000 2,4, 5, P = 0.05 4 Onset-IE L 9.0000 2, 3, 5, 5 CON-IE Log 11.6667 2, 3,4, VAN < PMX-1 = PMX-2 = ONSET = CON

Microbiological Results—Abraded Epithelium

Microbiological Results—Abraded Epithelium

Power and Sample Size One-way ANOVA Sigma = 0.783 Alpha = 0.05 Number ofLevels = 5 Corrected Sum of Squares of Means = 16.0707 Means = 5.9612,4.8456, 2.5986, 0.8997, 2.6737 Sample Size Power 3 1.0000 DuncanMultiple Comparisons Test Log₁₀ CFU/ml Row # Group/Level Mean Rank C.I.Overlaps 1 PMX-2-AE L 2.3333 2, 3, 2 VAN-AE Log 6.1667 1, 3, 3 PMX-1-AEL 6.5000 1, 2, P = 0.05 4 Onset-AE L 11.3333 5, 5 CON-AE Log 13.6667 4,PMX-2 = VAN = PMX-1 < ONSET = CONMicrobiological Results—Intact vs. Abraded Epithelium

Two Sample T-Test and Confidence Interval - PMX-1 Two sample T forPMX-1-IE Log vs PMX-1-AE Log N Mean StDev SE Mean PMX-1-IE 3 5.82 1.440.83 PMX-1-AE 3 2.599 0.947 0.55 95% CI for mu PMX-1-IE - mu PMX-1-AE:(0.05, 6.39) T-Test mu PMX-1-IE = mu PMX-1-AE (vs not =): T = 3.23 P =0.048 DF = 3 Abraded < Intact Two Sample T-Test and ConfidenceInterval - PMX-2 Two sample T for PMX-2-IE Log vs PMX-2-AE Log N MeanStDev SE Mean PMX-2-IE 3 6.17 1.04 0.60 PMX-2-AE 3 0.90 1.01 0.59 95% CIfor mu PMX-2-IE - mu PMX-2-AE: (2.60, 7.94) T-Test mu PMX-2-IE = muPMX-2-AE (vs not =): T = 6.28 P = 0.0082 DF = 3 Abraded < Intact TwoSample T-Test and Confidence Interval - VAN Two sample T for VAN-IE Logvs VAN-AE Log N Mean StDev SE Mean VAN-IE L 3 2.7239 0.0641 0.037 VAN-AEL 3 2.674 0.323 0.19 95% CI for mu VAN-IE L - mu VAN-AE L: (−0.768,0.87) T-Test mu VAN-IE L = mu VAN-AE L (vs not =): T = 0.26 P = 0.82 NSDF = 2 Two Sample T-Test and Confidence Interval - CON Two sample T forCON-IE Log vs CON-AE Log N Mean StDev SE Mean CON-IE L 3 6.898 0.3290.19 CON-AE L 3 5.961 0.978 0.56 95% CI for mu CON-IE L - mu CON-AE L:(−1.63, 3.50) T-Test mu CON-IE L = mu CON-AE L (vs not =): T = 1.57 P =0.26 NS DF = 2Microbiological Results—Intact vs. Abraded Epithelium

Two Sample T-Test and Confidence Interval - Onset Two sample T forOnset-IE Log vs Onset-AE Log N Mean StDev SE Mean Onset-IE 3 6.03 1.670.96 Onset-AE 3 4.816 0.278 0.16 95% CI for mu Onset-IE - mu Onset-AE:(−2.99, 5.42) T-Test mu Onset-IE = mu Onset-AE (vs not =): T = 1.24 P =0.34 NS DF = 2

Summary of Statistical Comparisons for Microbiological Data<=Significantly Fewer Colony Counts Effect of Abraded Epithelium onEffectiveness of Each Test Solution or Onset Control

PMX-1 Abraded < Intact PMX-1 Abraded < Intact Vancomycin Abraded =Intact Saline Control Abraded = Intact Onset of Therapy Control Abraded= IntactEffect of Test Solutions on Corneas with Intact Epithelium

PMX-1=PMX-2 PMX-1=Saline Control PMX-2=Saline Control Vancomycin<SalineControl Vancomycin<PMX-1 Vancomycin<PMX-2

Effect of Test Solutions on Corneas with Abraded Epithelium

PMX-1<Saline Control PMX-2<Saline Control PMX-2<PMX-1 Vancomycin<SalineControl PMX-1=Vancomycin PMX-2<Vancomycin Summary of Results

PMX-1 and PMX-2 were effective in reducing fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus colony counts in the NZWrabbit keratitis model only when the corneal epithelium was removed fromthe corneas. PMX-2 was more effective than 5% vancomycin in reducingcolony counts fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts in the NZW rabbit keratitis modelonly when the corneal epithelium was removed from the corneas. PMX-1 wasas effective as 5% vancomycin in reducing colony countsfluoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model only when the cornealepithelium was removed from the corneas. PMX-1 and PMX-2 inducedtoxicity similar to 5% vancomycin as manifested by higher Total OcularScores compared with the Saline treated eyes in eyes with intact cornealepithelia. Removal of the epithelium increased the Total Ocular Scoresof eyes treated 1% and 0.5% Oligomer 2 compared with the Total OcularScores of eyes treated with of 1% and 0.5% Oligomer 2 with intactepithelia.

The biomimetic Oligomer 2 was effective in reducing the numberfluoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model. However, Oligomer 2 waseffective in reducing fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts only when the corneal epithelium wasremoved. This suggests that Oligomer 2 does not penetrate the cornealepithelium into the corneal stroma. In the current study, PMX-1 andPMX-2 induced greater toxicity in infected rabbit eyes compared with theMildly Irritating toxicity induced in uninfected rabbit eyes inexperiment PMX-Tox-1.

Example 10 Ker-2

One purpose of the following experiments was to compare the efficacy of0.25% Oligomer 2, with and without 0.005% benzalkonium chloride, and 5%vancomycin in the treatment of a fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus infection in the NZW rabbitkeratitis model with or without intact corneal epithelia. The 0.005%benzalkonium chloride has been added to try to increase the penetrationof 0.25% Oligomer 2 through the corneal epithelium.

Fifteen rabbits were received from Myrtles' Rabbitry, Thompson Station,TN. The clinical isolate of fluoroquinolone-resistant,methicillin-resistant (MRSA) Staphylococcus aureus (K950) wassubcultured on 5% sheep blood agar and incubated at 37° C. in 6% CO₂overnight. The next morning, the MRSA strain was suspended in steriletrypticase soy broth to a 0.5 McFarland Standard, containingapproximately 5×10⁸ cfu/ml of bacteria. The absorbance of the suspensionwas measured at 650 nm using a Beckman DU-70 spectrophotometer. ODreadings of 0.07 corresponded to 5×10⁸ cfu/ml of bacteria. Thisconcentration was appropriately diluted in sterile trypticase soy brothto provide the inoculum of approximately 1,000 (1.0×10³) cfu/eye in 25μl. Colony counts were performed on the inoculum to determine the actualcfu inoculated. Following general anesthesia with ketamine and xylazineand topical anesthesia with proparacaine and prior to bacterialinoculation in the left eyes, 6 mm areas of the corneal epithelia wasremoved centrally with an Amoils epithelial scrubber. Nothing was doneto the right eyes. The 15 rabbits were then inoculated intrastromally inboth eyes with 25 μl of the bacterial dilution of approximately 10³cfu/eye of the bacteria. The bacterial inoculation of the left eyes wasdirectly under the epithelial defect created by the Amoils epithelialscrubber. The epithelia were removed in the left corneas in order todetermine whether this layer of the cornea is a barrier for Oligomer 2penetration when compared to the right cornea with an intact epithelium.A colony count was done on the inoculum to determine the actual cfuinoculated. The rabbits were immediately treated with analgesia in theform of and intramuscular injection of ketoprofen, 1.5 mg/kg. After 4hours, the 15 rabbits were divided into 4 treatment groups and oneuntreated control group sacrificed at the onset of therapy. Both eyes ofeach rabbit of the treatment groups were treated with one 37 μl drop ofthe solutions or control Saline or 1 drop of vancomycin from its dropperbottle.

Groups:

Left Right Rx—Both Treatment Rabbit Group Eye Eye Eyes Regimen # IAbraded Intact 0.25% Every 15 minutes 1-3 Epithe- Epithe- Oligomer for 5hours (21 lium lium 2 (PMX) total doses) II Abraded Intact 0.25% Every15 minutes 4-6 Epithe- Epithe- Oligomer 2 for 5 hours (21 lium lium with0.005% total doses) BAK (PMX-B) III Abraded Intact Vancomycin Every 15minutes 7-9 Epithe- Epithe- (50 mg/ml) for 5 hours (21 lium lium (Van)total doses) IV Abraded Intact Tris- Every 15 minutes 10-12 Epithe-Epithe- Buffered for 5 hours (21 lium lium Saline total doses) (Con) VAbraded Intact Sacrifice None 13-15 Epithe- Epithe- at Onset of liumlium Therapy (4 hours PI) (ONSET)Treatment was scheduled for every 15 minutes for 5 hours (21 totaldoses). The 3 rabbits in group V were sacrificed 4 hours PI and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were done on the homogenates using 5% sheep blood agarplates to determine the amount of bacteria contained in the corneas atthe onset of therapy. Following the completion of therapy, the eyes wereexamined for clinical signs of infection. One hour after the finaltreatment, the treated rabbits (Groups I-IV) were sacrificed and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were performed on the homogenates using 5% sheep bloodagar plates to determine the amount of bacteria contained in the corneasafter treatment. The next morning, the plates were counted and thenumber of cfu/eye of Staphylococcus aureus was determined for eachcornea.

Formulations: 1) 0.25% Oligomer 2 (PMX): Oligomer 2 Powder (Lot 8-15.1mg), on the day of treatment, was dissolved in 6.04 ml of Tris-BufferedSaline (TBS) to yield 0.25% Oligomer 2. The solution was stored at roomtemperature during the 5 hours of use. 37 μl drops were instilled usinga Rainin EDP electronic pipet set in the multi-dispense mode. Thissolution was designated PMX. 2) 0.25% Oligomer 2 with 0.005%Benzalkonium Chloride (BAK) (PMX-B): Oligomer 2 Powder (Lot 8-15.8 mg),on the day of treatment, was dissolved in 6.288 ml of Tris-BufferedSaline (TBS) before use. Then, 0.032 ml (32 μl) of 1% BenzalkoniumChloride was added to the solution to yield a total volume of 6.32 ml of0.25% Oligomer 2. The solution was stored at room temperature during the5 hours of use. 37 μl drops were instilled using a Rainin EDP electronicpipet set in the multi-dispense mode. This solution was designatedPMX-B. 3) 5% Vancomycin (50 mg/ml): Vancomycin (50 mg/ml) eye drops werepurchased from the UPMC pharmacy as the fortified preparation used inpatients. Vancomycin was administered using is supplied dropper bottle.4) Control (Tris-Buffered Saline): 37 μl drops of Tris-Buffered Salinewere instilled using a Rainin EDP electronic pipet set in themulti-dispense mode.

IACUC Protocol #0701145 “The In Vivo Evaluation of Biomimetics asTopical Ocular Antibiotics”.

MIC Characterization of Fluoroquinolone-Resistant, Methicillin-Resistant Staphylococcus aureus Strain K950 Antibiotic MIC [μg/ml](Minimum Inhibitory Concentration) Oligomer 2 0.25 μg/ml Vancomycin 2μg/ml Drop Schedule Drop # Time Time of Day 1 0    9:30 2  :15  9:45 3 :30 10:00 4  :45 10:15 5 1:00 10:30 6 1:15 10:45 7 1:30 11:00 8 1:4511:15 9 2:00 11:30 10 2:15 11:45 11 2:30 12:00 12 2:45 12:15 13 3:0012:30 14 3:15 12:45 15 3:30  1:00 16 3:45  1:15 17 4:00  1:30 18 4:15 1:45 19 4:30  2:00 20 4:45  2:15 21 5:00  2:30Sacrifice rabbits 1 hour after final drop (3:00).

DEFINITIONS OF ABBREVIATIONS

PMX-IE 0.25% Oligomer 2 with Intact EpitheliumPMX-AE 0.25% Oligomer 2 with Abraded EpitheliumPMX-B-IE 0.25% Oligomer 2 with 0.005% BAK with Intact EpitheliumPMX-B-AE 0.25% Oligomer 2 with 0.005% BAK with Abraded EpitheliumVAN-IE 5% Vancomycin with Intact EpitheliumVAN-AE 5% Vancomycin with Abraded EpitheliumCON-AE Tris-Buffered Saline Control with Abraded EpitheliumCON-IE Tris-Buffered Saline Control with Intact Epithelium

PMX 0.25% Oligomer 2

PMX-B 0.25% Oligomer 2 with 0.005% BAK

Clinical Evaluation—Results

Corneal Corneal Total Eye Group Conj. Chemosis Discharge Iritis EdemaInfiltrate Score 1R PMX-IE 3.0 3.0 2.5 1.0 1.5 2.5 13.5 2R PMX-IE 2.52.5 2.5 2.0 2.0 2.0 13.5 3R PMX-IE 2.5 3.0 2.5 1.5 1.5 2.5 13.5 1LPMX-AE 3.0 2.0 2.5 1.0 1.0 0.5 10.0 2L PMX-AE 2.5 2.5 2.0 2.0 1.5 0 10.53L PMX-AE 2.5 2.5 2.5 0.5 0.5 0 8.5 4R PMX-B-IE 3.0 3.0 3.0 1.5 1.5 2.514.5 5R PMX-B-IE 3.0 3.0 3.0 2.0 0.5 2.5 14.0 6R PMX-B-IE 3.0 3.0 3.01.0 1.0 2.5 13.5 4L PMX-B-AE 2.5 2.5 2.5 2.0 1.0 0 10.5 5L PMX-B-AE 2.52.5 2.5 1.0 1.0 0 9.5 6L PMX-B-AE 2.5 2.5 3.0 1.0 0.5 0 9.5 7R VAN-IE2.5 2.5 3.0 1.0 0.5 0.5 10.0 8R VAN-IE 2.5 2.5 2.5 1.5 0.5 0 9.5 9RVAN-IE 2.5 2.5 2.5 0.5 0.5 0 8.5 7L VAN-AE 2.5 2.5 2.5 1.0 0.5 0.5 9.58L VAN-AE 2.5 2.5 2.5 1.0 1.0 0 9.5 9L VAN-AE 2.5 2.5 2.5 0.5 1.0 0 9.010R  CON-IE 0.5 0 1.0 0.5 0.5 3.0 5.5 11R  CON-IE 2.0 0.5 2.0 2.5 3.02.0 12.0 12R  CON-IE 1.5 0 2.5 2.0 0.5 3.0 9.5 10L  CON-AE 2.0 1.5 2.01.5 2.0 2.5 11.5 11L  CON-AE 2.0 2.0 1.5 1.5 1.0 0.5 8.5 12L  CON-AE 2.52.5 2.5 1.5 1.0 0.5 10.5 Scale 0 = Normal; 0.5 = Trace; 1.0 = Mild; 1.5= Mild/Moderate; 2.0 = Moderate; 2.5 = Moderate/Severe; 3.0 = Severe

Clinical Evaluation—Statistics

Descriptive Statistics Total Ocular Score Variable N Mean Median TrMeanStDev SE Mean PMX-IE Score 3 13.500 13.500 13.500 0.000 0.000 PMX-AEScore 3 9.667 10.000 9.667 1.041 0.601 PMX-B-IE Score 3 14.000 14.00014.000 0.500 0.289 PMX-B-AE Score 3 9.833 9.500 9.833 0.577 0.333 VAN-IEScore 3 9.333 9.500 9.333 0.764 0.441 VAN-AE Score 3 9.333 9.500 9.3330.289 0.167 CON-IE Score 3 9.00 9.50 9.00 3.28 1.89 CON-AE Score 310.167 10.500 10.167 1.528 0.882 Duncan Multiple Comparisons Test TotalScore Row # Group/Level Mean Rank C.I. Overlaps 1 VAN-AE Sco 7.3333 2,3, 4, 5, 6, 2 VAN-IE Sco 8.0000 1, 3, 4, 5, 6, 3 CON-IE Sco 9.1667 1, 2,4, 5, 6, P = 0.05 4 PMX-AE Sco 10.1667 1, 2, 3, 5, 6, 5 PMX-B-AE S10.6667 1, 2, 3, 4, 6, 6 CON-AE Sco 11.6667 1, 2, 3, 4, 5, 7 PMX-IE Sco20.5000 8, 8 PMX-B-IE S 22.5000 7, VAN-AE = VAN-IE = CON-IE = PMX-AE =PMX-B-AE = CON AE < PMX-IE = PMX-B-IE

Median Total Ocular Score

Treatment Abraded (score) Intact (score) PMX 10 13.5 PMX-B 9.5 14Vancomycin 9.5 9.5 Control 10.5 9.5

Microbiological Results

Inoculum = 1371 cfu/cornea Data Display CFU/ml Row PMX-IE PMX-AEPMX-B-IE PMX-B-AE 1 4750000 5 11000000 13500 2 4450000 8900 15350000 803 9650000 1200 12850000 190 VAN- Onset- Row IE VAN-AE CON-IE CON-AEOnset-IE AE 1 71000 550 5250000 3300000 100500 63000 2 2200 200 13200000510000 77000 74500 3 350 600 14600000 965000 93500 44500 Data DisplayLog₁₀ CFU/ml Row PMX-IE Log PMX-AE Log PMX-B-IE Log PMX-B-AE Log 16.67669 0.69897 7.04139 4.13033 2 6.64836 3.94939 7.18611 1.90309 36.98453 3.07918 7.10890 2.27875 Row VAN-IE Log VAN-AE Log CON-IE LogCON-AE Log 1 4.85126 2.74036 6.72016 6.51851 2 3.34242 2.30103 7.120575.70757 3 2.54407 2.77815 7.16435 5.98453 Row Onset-IE Log Onset-AE Log1 5.00217 4.79934 2 4.88649 4.87216 3 4.97081 4.64836 DescriptiveStatistics Log₁₀ CFU/ml Variable N Mean Median TrMean StDev SE MeanPMX-IE Log 3 6.770 6.677 6.770 0.186 0.108 PMX-AE Log 3 2.576 3.0792.576 1.683 0.971 PMX-B-IE Log 3 7.1121 7.1089 7.1121 0.0724 0.0418PMX-B-AE Log 3 2.771 2.279 2.771 1.192 0.688 VAN-IE Log 3 3.579 3.3423.579 1.172 0.676 VAN-AE Log 3 2.607 2.740 2.607 0.265 0.153 CON-IE Log3 7.002 7.121 7.002 0.245 0.141 CON-AE Log 3 6.070 5.985 6.070 0.4120.238 Onset-IE Log 3 4.9532 4.9708 4.9532 0.0598 0.0345 Onset-AE Log 34.7733 4.7993 4.7733 0.1142 0.0659

Microbiological Results—Intact Epithelium

Microbiological Results—Intact Epithelium

Duncan Multiple Comparisons Test Log₁₀ CFU/ml Row # Group/Level MeanRank C.I. Overlaps 1 VAN-IE Log 2.0000 2, 2 Onset-IE L 5.0000 1, 3PMX-IE Log 8.3333 4, 5, P = 0.05 4 CON-IE Log 12.0000 3, 5, 5 PMX-B-IE L12.6667 3, 4, VAN = ONSET < PMX = CON = PMX-B

Microbiological Results—Abraded Epithelium

Microbiological Results—Abraded Epithelium

Duncan Multiple Comparisons Test Log₁₀ CFU/ml Row # Group/Level MeanRank C.I. Overlaps 1 PMX-B-AE L 4.6667 2, 3, 4 2 VAN-AE Log 5.0000 1, 3,4, P = 0.05 3 PMX-AE Log 5.3333 1, 2, 4, 4 Onset-AE L 11.0000 1, 2, 3,5, 5 CON-AE Log 14.0000 4, PMX-B = VAN = PMX < CON; All Groups = ONSETMicrobiological Results—Intact vs. Abraded Epithelium

Two Sample T-Test and Confidence Interval - PMX Two sample T for PMX-IELog vs PMX-AE Log N Mean StDev SE Mean PMX-IE L 3 6.770 0.186 0.11PMX-AE L 3 2.58 1.68 0.97 95% CI for mu PMX-IE L - mu PMX-AE L: (−0.01,8.40) T-Test mu PMX-IE L = mu PMX-AE L (vs not =): T = 4.29 P = 0.050 DF= 2 Abraded < Intact Two Sample T-Test and Confidence Interval - PMX-BTwo sample T for PMX-B-IE Log vs PMX-B-AE Log N Mean StDev SE MeanPMX-B-IE 3 7.1121 0.0724 0.042 PMX-B-AE 3 2.77 1.19 0.69 95% CI for muPMX-B-IE - mu PMX-B-AE: (1.374, 7.31) T-Test mu PMX-B-IE = mu PMX-B-AE(vs not =): T = 6.29 P = 0.024 DF = 2 Abraded < Intact Two Sample T-Testand Confidence Interval - VAN Two sample T for VAN-IE Log vs VAN-AE LogN Mean StDev SE Mean VAN-IE L 3 3.58 1.17 0.68 VAN-AE L 3 2.607 0.2650.15 95% CI for mu VAN-IE L - mu VAN-AE L: (−2.01, 3.96) T-Test muVAN-IE L = mu VAN-AE L (vs not =): T = 1.40 P = 0.30 NS DF = 2 TwoSample T-Test and Confidence Interval - CON Two sample T for CON-IE Logvs CON-AE Log N Mean StDev SE Mean CON-IE L 3 7.002 0.245 0.14 CON-AE L3 6.070 0.412 0.24 95% CI for mu CON-IE L - mu CON-AE L: (0.05, 1.81)T-Test mu CON-IE L = mu CON-AE L (vs not =): T = 3.37 P = 0.044 DF = 3Abraded < Intact Two Sample T-Test and Confidence Interval - Onset Twosample T for Onset-IE Log vs Onset-AE Log N Mean StDev SE Mean Onset-IE3 4.9532 0.0598 0.035 Onset-AE 3 4.773 0.114 0.066 95% CI for muOnset-IE - mu Onset-AE: (−0.057, 0.417) T-Test mu Onset-IE = mu Onset-AE(vs not =): T = 2.42 P = 0.094 NS DF = 3

Microbiological Results—0.25% Oligomer 2 w/o BAK vs. w/ BAK—IntactEpithelium

Two Sample T-Test and Confidence Interval - PMX-IE vs. PMX-B-IE Twosample T for PMX-IE Log vs PMX-B-IE Log N Mean StDev SE Mean PMX-IE L 36.770 0.186 0.11 PMX-B-IE 3 7.1121 0.0724 0.042 95% CI for mu PMX-IE L -mu PMX-B-IE: (−0.84, 0.155) T-Test mu PMX-IE L = mu PMX-B-IE (vs not =):T = −2.96 P = 0.097 NS DF = 2

Microbiological Results—0.25% Oligomer 2 w/o BAK vs. w/ BAK—AbradedEpithelium

Two Sample T-Test and Confidence Interval - PMX-AE vs. PMX-B-AE Twosample T for PMX-AE Log vs PMX-B-AE Log N Mean StDev SE Mean PMX-AE L 32.58 1.68 0.97 PMX-B-AE 3 2.77 1.19 0.69 95% CI for mu PMX-AE L - muPMX-B-AE: (−3.98, 3.59) T-Test mu PMX-AE L = mu PMX-B-AE (vs not =): T =−0.16 P = 0.88 NS DF = 3

Summary of Statistical Comparisons for Microbiological Data<=Significantly Fewer Colony Counts Effect of Abraded Epithelium onEffectiveness of Each Test Solution or Onset Control

PMX Abraded < Intact PMX-B Abraded < Intact Vancomycin Abraded = IntactSaline Control Abraded < Intact Onset of Therapy Control Abraded =IntactEffect of Test Solutions on Corneas with Intact Epithelium

PMX═PMX-B PMX=Saline Control PMX-B=Saline Control Vancomycin<SalineControl Vancomycin<PMX Vancomycin<PMX-B

Effect of Test Solutions on Corneas with Abraded Epithelium

PMX<Saline Control PMX-B<Saline Control PMX-B=PMX Vancomycin<SalineControl PMX=Vancomycin PMX-B=Vancomycin

Effect of BAK on 0.25% Oligomer 2 on Corneas with Intact Epithelium

PMX═PMX-B

Effect of BAK on 0.25% Oligomer 2 on Corneas with Abraded Epithelium

PMX═PMX-B Summary of Results

0.25% Oligomer 2 (PMX) and 0.25% Oligomer 2 with 0.005% benzalkoniumchloride (BAK) (PMX-2) were effective in reducingfluoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model only when the cornealepithelium was removed from the corneas. There was no difference influoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model between 0.25% Oligomer 2(PMX) and 0.25% Oligomer 2 with 0.005% benzalkonium chloride (BAK)(PMX-2) with intact or abraded corneal epithelium.

0.25% Oligomer 2 (PMX) and 0.25% Oligomer 2 with 0.005% benzalkoniumchloride (BAK) (PMX-2) were as effective as 5% vancomycin in reducingcolony counts fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts in the NZW rabbit keratitis modelonly when the corneal epithelium was removed from the corneas. 0.25%Oligomer 2 (PMX) and 0.25% Oligomer 2 with 0.005% benzalkonium chloride(BAK) (PMX-2) induced toxicity that was worse than 5% vancomycin asmanifested by higher Total Ocular Scores compared with the vancomycinand Saline treated eyes in eyes with intact corneal epithelia.

The biomimetic Oligomer 2 was effective in reducing the numberfluoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model. This result wasachieved using a lower concentration (0.25%) than in previous studies(1% and 0.5%). As in the previous studies, Oligomer 2 was effective inreducing fluoroquinolone-resistant, methicillin-resistant Staphylococcusaureus colony counts only when the corneal epithelium was removed. Theaddition of 0.005% benzalkonium chloride (BAK) did not aid in thepenetration of 0.25% Oligomer 2 through the intact corneal epithelium tothe site of the infection in the corneal stroma. In the current study,0.25% Oligomer 2 (PMX) and 0.25% Oligomer 2 with 0.005% benzalkoniumchloride (BAK) (PMX-2) induced greater toxicity in infected rabbit eyeswith intact corneal epithelium compared with 5% vancomycin and theSaline treated Control with intact corneal epithelium. As suggested inthe previous study, additional studies using much lower concentrationsof Oligomer 2 and/or different formulations should be considered inorder to reduce its toxicity, yet retain efficacy in thefluoroquinolone-resistant, methicillin-resistant Staphylococcus aureusNZW rabbit keratitis model.

Example 11 Ker-3

One purpose of the following experiments was to determine the efficacyof 0.25% Oligomer 4, with and without 200 μM Farnesol, and 200 μMFarnesol in the treatment of a fluoroquinolone-resistant andmethicillin-resistant Staphylococcus aureus infection in the NZW rabbitkeratitis model with or without intact corneal epithelia. The 200 μMFarnesol has been added to try to increase the efficacy and penetrationof 0.25% Oligomer 4 through the corneal epithelium.

Fifteen rabbits were received from Myrtles' Rabbitry, Thompson Station,TN. The clinical isolate of fluoroquinolone-resistant andmethicillin-resistant (MRSA) Staphylococcus aureus (K₉₅₀) wassubcultured on 5% sheep blood agar and incubated at 37° C. in 6% CO₂overnight. The next morning, the MRSA strain was suspended in steriletrypticase soy broth to a 0.5 McFarland Standard, containingapproximately 5×10⁸ CFU/ml of bacteria. The absorbance of the suspensionwas measured at 650 nm using a Beckman DU-70 spectrophotometer. ODreadings of 0.07 corresponded to 5×10⁸ CFU/ml of bacteria. Thisconcentration was appropriately diluted in sterile trypticase soy brothto provide the inoculum of approximately 1,000 (1.0×10³) CFU/eye in 25μl. Colony counts were performed on the inoculum to determine the actualCFU inoculated. Following general anesthesia with ketamine and xylazineand topical anesthesia with proparacaine and prior to bacterialinoculation in the left eyes, 6 mm areas of the corneal epithelia wereremoved centrally from the left eyes with an Amoils epithelial scrubber.Nothing was done to the right eyes. The 15 rabbits the were theninoculated intrastromally in both eyes with 25 μl of the bacterialdilution of approximately 10³ cfu/eye of the bacteria. The bacterialinoculation of the left eyes was directly under the epithelial defectcreated by the Amoils epithelial scrubber. The epithelia were removed inthe left corneas in order to determine whether this layer of the corneais a barrier for drug penetration when compared to the right cornea withan intact epithelium. A colony count was done on the inoculum todetermine the actual CFU inoculated. The rabbits were immediatelytreated with analgesia in the form of an intramuscular injection ofketoprofen, 1.5 mg/kg. After 4 hours, the 15 rabbits were divided into 4treatment groups and one untreated control group sacrificed at the onsetof therapy. Both eyes of each rabbit of the treatment groups weretreated with one 37 μl drop of the solutions or control Saline.

Groups:

Left Right Rx—Both Treatment Rabbit Group Eye Eye Eyes Regimen # IAbraded Intact 0.25% Every 15 minutes 1-3 Epithe- Epithe- Oligomer for 5hours (21 lium lium 4 (PMX) total doses) II Abraded Intact 0.25% Every15 minutes 4-6 Epithe- Epithe- Oligomer for 5 hours (21 lium lium 4 +200 μM total doses) Farnesol (P + F) III Abraded Intact 200 μM Every 15minutes 7-9 Epithe- Epithe- Farnesol for 5 hours (21 lium lium (FARN)total doses) IV Abraded Intact Tris- Every 15 minutes 10-12 Epithe-Epithe- Buffered for 5 hours (21 lium lium Saline total doses) (CON) VAbraded Intact Sacrifice None 13-15 Epithe- Epithe- at Onset of liumlium Therapy (4 hours PI) (ONSET)Treatment was scheduled for every 15 minutes for 5 hours (21 totaldoses). The 3 rabbits in group V were sacrificed 4 hours PI and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were done on the homogenates using 5% sheep blood agarplates to determine the amount of bacteria contained in the corneas atthe onset of therapy. Following the completion of therapy, the eyes wereexamined for clinical signs of infection. One hour after the finaltreatment, the treated rabbits (Groups I-IV) were sacrificed and large9.5 mm buttons were removed from the corneas. These were placed in 1 mlof PBS and kept on ice. The corneal buttons were homogenized for 25seconds on ice using the motorized homogenizer. After homogenization,colony counts were done on the homogenates using 5% sheep blood agarplates to determine the amount of bacteria contained in the corneasafter treatment. The next morning, the plates were counted and thenumber of CFU/eye of Staphylococcus aureus was determined for eachcornea.

Formulations: 1) 0.25% Oligomer 2 (PMX): Tube G1 of Oligomer 2 powderwas stored at 4° C. until use. Upon use, the tube was removed from therefrigerator and 3.28 ml of S1 (sterile water for injection) was addedand vortexed until the solid was completely dissolved. Then 3.28 ml ofS2 (2×TBS) was added and vortexed for 10 seconds. This solution wasdesignated PMX. 37 μl drops were instilled were instilled using a RaininEDP electronic pipet set in the multi-dispense mode; 2) 0.25% Oligomer 2with 200 μM Farnesol (P+F): Tube G2 of Oligomer 2 powder was stored at4° C. until use. Upon use, the tube was removed from the refrigeratorand 3.33 ml of Si (sterile water for injection) was added and vortexeduntil the solid was completely dissolved. Then 3.33 ml of S3 (400 μMFarnesol+2% Propylene Glycol in 2×TBS) was added and vortexed for 10seconds. This solution was designated P+F. 37 μl drops were instilledwere instilled using a Rainin EDP electronic pipet set in themulti-dispense mode; 3) 200 μM Farnesol (FARN): Tube G3 containing about8 ml of 200 μM Farnesol in 1% Propylene Glycol (PG) and TBS was storedat 4° C. until use. This solution was designated FARN. 37 μl drops wereinstilled using a Rainin EDP electronic pipet set in the multi-dispensemode; 4) Control (Tris-Buffered Saline, CON): Tube G4 containing about 8ml of Tris-Buffered Saline (10 mM TRIS, 150 mM NaCl, pH=7.4) was storedat 4° C. until use. This solution was designated CON. 37 μl drops wereinstilled using a Rainin EDP electronic pipet set in the multi-dispensemode.

IACUC Protocol #0701145-1. “The In Vivo Evaluation of Biomimetics asTopical Ocular Antibiotics”.

MIC Characterization of Fluoroquinolone-Resistant, Methicillin-Resistant Staphylococcus aureus Strain K950 Antibiotic MIC [μg/ml](Minimum Inhibitory Concentration) Oligomer 4 0.5 μg/ml Drop ScheduleDrop # Time Time of Day 1 0    9:30 2  :15  9:45 3  :30 10:00 4  :4510:15 5 1:00 10:30 6 1:15 10:45 7 1:30 11:00 8 1:45 11:15 9 2:00 11:3010 2:15 11:45 11 2:30 12:00 12 2:45 12:15 13 3:00 12:30 14 3:15 12:45 153:30  1:00 16 3:45  1:15 17 4:00  1:30 18 4:15  1:45 19 4:30  2:00 204:45  2:15 21 5:00  2:30 Sacrifice rabbits 1 hour after final drop(3:30).

DEFINITIONS OF ABBREVIATIONS

PMX-IE 0.25% Oligomer 4 with Intact EpitheliumPMX-AE 0.25% Oligomer 4 with Abraded EpitheliumP+F-IE 0.25% Oligomer 4+200 μM Farnesol with Intact EpitheliumP+F-AE 0.25% Oligomer 4+200 μM Farnesol with Abraded EpitheliumFARN-IE 200 μM Farnesol with Intact EpitheliumFARN-AE 200 μM Farnesol with Abraded EpitheliumCON-AE Tris-Buffered Saline Control with Abraded EpitheliumCON-IE Tris-Buffered Saline Control with Intact Epithelium

Clinical Evaluation—Results

Corneal Corneal Total Eye Group Conj. Chemosis Discharge Iritis EdemaInfiltrate Score 1R PMX-IE 2.5 2.5 2.0 2.0 1.0 2.0 12.0 2R PMX-IE 2.02.0 2.0 2.0 0.5 0.5 9.0 3R PMX-IE 2.0 2.0 2.0 2.0 0.5 1.0 9.5 1L PMX-AE2.0 2.5 3.0 2.0 1.5 0 11.0 2L PMX-AE 2.0 2.0 3.0 2.0 0.5 0 9.5 3L PMX-AE2.0 2.0 2.5 1.5 1.0 0 9.0 4R P + F-IE 1.5 1.5 1.5 1.0 0.5 0.5 6.5 5R P +F-IE 2.0 1.5 1.5 2.0 1.0 2.5 10.5 6R P + F-IE 2.0 2.0 2.5 2.0 1.0 1.511.0 4L P + F-AE 2.0 2.0 2.0 1.5 1.0 0 8.5 5L P + F-AE 2.5 2.5 2.5 2.01.0 0 10.5 6L P + F-AE 2.0 2.5 3.0 2.0 1.0 0 10.5 7R FARN-IE 1.5 1.5 1.51.5 1.0 2.0 9.0 8R FARN-IE 1.5 1.0 1.0 1.5 0.5 1.5 7.0 9R FARN-IE 1.51.5 1.5 2.0 1.0 2.0 9.5 7L FARN-AE 2.0 2.0 2.0 2.0 2.0 1.0 11.0 8LFARN-AE 1.5 1.5 1.5 1.5 1.0 0.5 7.5 9L FARN-AE 1.5 1.5 1.5 1.5 1.0 1.08.0 10R  CON-IE 1.5 1.0 1.0 1.0 1.0 1.0 6.5 11R  CON-IE 1.0 1.0 1.0 1.51.0 1.0 6.5 12R  CON-IE 1.5 1.5 1.0 2.0 1.0 2.0 9.0 10L  CON-AE 1.0 1.52.0 1.0 0.5 0 6.0 11L  CON-AE 1.5 1.5 2.0 1.5 1.5 1.0 9.0 12L  CON-AE1.5 1.5 2.0 1.5 1.5 1.0 9.0 Scale 0 = Normal; 0.5 = Trace; 1.0 = Mild;1.5 = Mild/Moderate; 2.0 = Moderate; 2.5 = Moderate/Severe; 3.0 = Severe

Clinical Evaluation—Statistics

Descriptive Statistics Total Ocular Score Total SE Mini- Maxi- VariableCount Mean Mean StDev mum Median mum PMX-IE 3 10.167 0.928 1.607 9.0009.500 12.000 Score PMX-AE 3 9.833 0.601 1.041 9.000 9.500 11.000 ScoreP + F- 3 9.33 1.42 2.47 6.50 10.50 11.00 IE Score P + F-AE 3 9.833 0.6671.155 8.500 10.500 10.500 Score FARN-IE 3 8.500 0.764 1.323 7.000 9.0009.500 Score FARN-AE 3 8.83 1.09 1.89 7.50 8.00 11.00 Score CON-IE 37.333 0.833 1.443 6.500 6.500 9.000 Score CON-AE 3 8.00 1.00 1.73 6.009.00 9.00 Score Duncan Multiple Comparisons Test Total Score  Row #Group/Level Mean Rank C.I. Overlaps 1 CON-IE Sco 5.8333 2, 3, 4, 5, 6,7, 8, 2 CON-AE Sco 8.0000 1, 3, 4, 5, 6, 7, 8, 3 FARN-IE Sc 10.8333 1,2, 4, 5, 6, 7, 8, 4 FARN-AE Sc 11.6667 1, 2, 3, 5, 6, 7, 8, P = 0.05 5P + F-IE Sco 14.6667 1, 2, 3, 4, 6, 7, 8, 6 P + F-AE Sco 15.3333 1, 2,3, 4, 5, 7, 8, 7 PMX-AE Sco 16.5000 1, 2, 3, 4, 5, 6, 8, 8 PMX-IE Sco17.1667 1, 2, 3, 4, 5, 6, 7, N0 Differences Among the Groups

Microbiological Results

Inoculum = 1098 CFU/cornea Data Display CFU/ml Row PMX-IE PMX-AE P +F-IE P + F-AE FARN-IE FARN-AE CON-IE CON-AE 1 1650000 0 50 9500 452000007750000 115000000 30500 2 12500 12500 13600000 50 18600000 6650000253000000 69000000 3 92000 350 5200000 8050 21400000 8250000 15000000176000000 Row Onset-IE Onset-AE 1 75000 118000 2 59000 61000 3 555002500 Data Display Log₁₀ CFU/ml  Row PMX-IE Log PMX-AE Log P + F-IE LogP + F-AE Log FARN-IE Log FARN-AE Log 1 6.21748 0.00000 1.69897 3.977727.65514 6.88930 2 4.09691 4.09691 7.13354 1.69897 7.26951 6.82282 34.96379 2.54407 6.71600 3.90580 7.33041 6.91645 Row CON-IE Log CON-AELog Onset-IE Log Onset-AE Log 1 8.06070 4.48430 4.87506 5.07188 28.40312 7.83885 4.77085 4.78533 3 7.17609 8.24551 4.74429 3.39794Descriptive Statistics Log₁₀ CFU/ml Variable Total Count Mean SE MeanStDev Minimum Median Maximum PMX-IE Log 3 5.093 0.616 1.066 4.097 4.9646.217 PMX-AE Log 3 2.21 1.19 2.07 0.00 2.54 4.10 P + F-IE Log 3 5.181.75 3.02 1.70 6.72 7.13 P + F-AE Log 3 3.194 0.748 1.295 1.699 3.9063.978 FARN-IE Log 3 7.418 0.120 0.207 7.270 7.330 7.655 FARN-AE Log 36.8762 0.0278 0.0482 6.8228 6.8893 6.9165 CON-IE Log 3 7.880 0.366 0.6337.176 8.061 8.403 CON-AE Log 3 6.86 1.19 2.06 4.48 7.84 8.25 Onset-IELog 3 4.7967 0.0399 0.0691 4.7443 4.7709 4.8751 Onset-AE Log 3 4.4180.517 0.895 3.398 4.785 5.072

Microbiological Results—Intact Epithelium

Kruskal-Wallis ANOVA with Duncan Multiple Comparisons Test - Log₁₀CFU/ml Row # Group/Level Mean Rank C.I. Overlaps 1 Onset-IE L 4.0000 2,3, 2 PMX-IE Log 5.0000 1, 3, 3 P + F-IE Log 6.0000 1, 2, P = 0.05 4FARN-IE Lo 12.0000 5, 5 CON-IE Log 13.0000 4, ONSET = PMX = P + F < FARN= CON

Microbiological Results—Abraded Epithelium

Kruskal-Wallis ANOVA with Duncan Multiple Comparisons Test - Log₁₀CFU/ml Row # Group/Level Mean Rank C.I. Overlaps 1 PMX-AE Log 3.6667 2,3, 2 P + F-AE Log 4.3333 1, 3, 3 Onset-AE L 7.6667 1, 2, P = 0.05 4FARN-AE Lo 12.0000 5, 5 CON-AE Log 12.3333 4, PMX = P + F = ONSET < FARN= CON

Microbiological Results—0.25% Oligomer 4 w/o FARN vs. w/ FARN—IntactEpithelium

Mann-Whitney Test and CI: PMX-IE Log, P + F-IE Log N Median PMX-IE Log 34.964 P + F-IE Log 3 6.716 Point estimate for ETA1-ETA2 is −0.916 91.9Percent CI for ETA1-ETA2 is (−3.034, 4.518) W = 9.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.6625 NS

Microbiological Results—0.25% Oligomer 4 w/o FARN vs. w/ FARN—AbradedEpithelium

Mann-Whitney Test and CI: PMX-AE Log, P + F-AE Log N Median PMX-AE Log 32.544 P + F-AE Log 3 3.906 Point estimate for ETA1-ETA2 is −1.362 91.9Percent CI for ETA1-ETA2 is (−3.977, 2.399) W = 10.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 1.0000 NSMicrobiological Results—Intact vs. Abraded Epithelium

Mann-Whitney Test and CI: PMX-IE Log, PMX-AE Log N Median PMX-IE Log 34.964 PMX-AE Log 3 2.544 Point estimate for ETA1-ETA2 is 2.420 91.9Percent CI for ETA1-ETA2 is (0.001, 6.218) W = 14.5 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.1266 The test is significant at0.1212 NS (adjusted for ties) Mann-Whitney Test and CI: P + F-IE Log,P + F-AE Log N Median P + F-IE Log 3 6.716 P + F-AE Log 3 3.906 Pointestimate for ETA1-ETA2 is 2.810 91.9 Percent CI for ETA1-ETA2 is(−2.277, 5.436) W = 12.5 Test of ETA1 = ETA2 vs ETA1 not = ETA2 issignificant at 0.5127 The test is significant at 0.5066 NS (adjusted forties) Mann-Whitney Test and CI: FARN-IE Log, FARN-AE Log N MedianFARN-IE Log 3 7.3304 FARN-AE Log 3 6.8893 Point estimate for ETA1-ETA2is 0.4467 91.9 Percent CI for ETA1-ETA2 is (0.3532, 0.8323) W = 15.0Test of ETA1 = ETA2 vs ETA1 not = ETA2 is significant at 0.0809 NSMann-Whitney Test and CI: CON-IE Log, CON-AE Log N Median CON-IE Log 38.061 CON-AE Log 3 7.839 Point estimate for ETA1-ETA2 is 0.222 91.9Percent CI for ETA1-ETA2 is (−1.070, 3.917) W = 12.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.6625 NS Mann-Whitney Test and CI:Onset-IE Log, Onset-AE Log N Median Onset-IE Log 3 4.771 Onset-AE Log 34.785 Point estimate for ETA1-ETA2 is −0.015 91.9 Percent CI forETA1-ETA2 is (−0.328, 1.477) W = 10.0 Test of ETA1 = ETA2 vs ETA1 not =ETA2 is significant at 1.0000 NS class = Section8>

Summary of Statistical Comparisons for Microbiological Data<=Significantly Fewer Colony Counts Effect of Abraded Epithelium onEffectiveness of Each Test Solution or Onset Control

PMX Abraded = Intact P + F Abraded = Intact FARN Abraded = Intact SalineControl Abraded = Intact Onset of Therapy Control Abraded = IntactEffect of Test Solutions on Corneas with Intact Epithelium

ONSET=PMX═P+F<FARN═CON

Effect of Test Solutions on Corneas with Abraded Epithelium

PMX═P+F═ONSET<FARN═CON

Effect of Farnesol on 0.25% Oligomer 4 on Corneas with Intact Epithelium

PMX═P+F

Effect of Farnesol on 0.25% Oligomer 4 on Corneas with AbradedEpithelium

PMX═P+F Summary of Results

0.25% Oligomer 4 (PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F)were effective in reducing fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus colony counts compared withthe Saline Control in the NZW rabbit keratitis model when the cornealepithelium was intact or removed from the corneas. 0.25% Oligomer 4(PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F) were not effectivein reducing fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts compared with the Onset of TherapyControl in the NZW rabbit keratitis model when the corneal epitheliumwas intact or removed from the corneas. There was no difference influoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model between 0.25% Oligomer 4(PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F) with intact orabraded corneal epithelium. 200 mM Farnesol alone was NOT effective inreducing colony counts fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts compared with the Saline Control inthe NZW rabbit keratitis model. 0.25% Oligomer 4 (PMX) and 0.25%Oligomer 4 with 200 mM Farnesol (P+F) and 200 mM Farnesol alone did notinduce statistically greater toxicity (as manifested by higher TotalOcular Scores) compared with the Saline treated eyes in eyes with intactor abraded corneal epithelia.

The biomimetic Oligomer 4 alone or in combination with 200 mM Farnesolwere effective in reducing the number fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus colony counts in the NZWrabbit keratitis model compared with the Saline Control compared withthe Saline Control. However, Oligomer 4 alone or in combination with 200mM Farnesol were not effective in reducing fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus colony counts whether whenthe corneal epithelium was intact or removed compared with the Onset ofTherapy Control in the fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus NZW rabbit keratitis model indicating thecompounds did not significantly reduce the bacterial load present at theonset of therapy. The addition of 200 mM Farnesol did not appear aid inthe penetration of 0.25% Oligomer 4 through the intact cornealepithelium to the site of the infection in the corneal stroma norenhance its antibacterial efficacy in the fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus NZW rabbit keratitis model.In the current study, Oligomer 4 alone or in combination with 200 mMFarnesol did not induced significantly greater toxicity in infectedrabbit eyes compared with the Saline treated Control in thefluoroquinolone-resistant, methicillin-resistant Staphylococcus aureusNZW rabbit keratitis model. The results from this study essentiallyreproduce those obtained in previous studies.

Example 12 Ker-4 DEFINITIONS OF ABBREVIATIONS

PMX-IE 0.25% Oligomer 4 with Intact EpitheliumPMX-AE 0.25% Oligomer 4 with Abraded EpitheliumP+F-IE 0.25% Oligomer 4+200 μM Farnesol with Intact EpitheliumP+F-AE 0.25% Oligomer 4+200 μM Farnesol with Abraded EpitheliumFARN-IE 200 μM Farnesol with Intact EpitheliumFARN-AE 200 μM Farnesol with Abraded EpitheliumCON-AE Tris-Buffered Saline Control with Abraded EpitheliumCON-IE Tris-Buffered Saline Control with Intact Epithelium

Clinical Evaluation—Statistics

Data Display Total Ocular Score Row PMX-IE PMX-AE P + F-IE P + F-AEFARN-IE FARN-AE CON-IE CON-AE 1 6.5 9.5 13.0 9.5 10.0 11.0 9.5 10.0 213.0 10.5 8.0 8.5 10.0 8.5 11.0 14.0 Ker-3 3 16.5 12.0 12.5 10.0 8.5 8.59.5 10.5 4 12.0 11.0 6.5 8.5 9.0 11.0 6.5 6.0 5 9.0 9.5 10.5 10.5 7.07.5 6.5 9.0 Ker-4 6 9.5 9.0 11.0 10.5 9.5 8.0 9.0 9.0 DescriptiveStatistics Total Ocular Score Variable Total Count Mean SE Mean StDevMinimum Median Maximum PMX-IE Score 6 11.08 1.43 3.51 6.50 10.75 16.50PMX-AE Score 6 10.250 0.461 1.129 9.000 10.000 12.000 P + F-IE Score 610.25 1.04 2.54 6.50 10.75 13.00 P + F-AE Score 6 9.583 0.375 0.9178.500 9.750 10.500 FARN-IE Score 6 9.000 0.465 1.140 7.000 9.250 10.000FARN-AE Score 6 9.083 0.625 1.530 7.500 8.500 11.000 CON-IE Score 68.667 0.738 1.807 6.500 9.250 11.000 CON-AE Score 6 9.75 1.06 2.60 6.009.50 14.00 Duncan Multiple Comparisons Test Total Score Row #Group/Level Mean Rank C.I. Overlaps 1 CON-IE Sco 18.5833 2, 3, 4, 5, 6,7, 8, 2 FARN-AE Sc 19.5833 1, 3, 4, 5, 6, 7, 8, 3 FARN-IE Sc 19.7500 1,2, 4, 5, 6, 7, 8, 4 P + F-AE Sco 24.2500 1, 2, 3, 5, 6, 7, 8, P = 0.05 5CON-AE Sco 24.4167 1, 2, 3, 4, 6, 7, 8, 6 P + F-IE Sco 29.0833 1, 2, 3,4, 5, 7, 8, 7 PMX-IE Sco 30.1667 1, 2, 3, 4, 5, 6, 8, 8 PMX-AE Sco30.1667 1, 2, 3, 4, 5, 6, 7, No Differences Among the Groups

Microbiological Results

Data Display CFU/ml Row PMX-IE PMX-AE P + F-IE P + F-AE FARN-IE FARN-AE1 0 0 11950000 255 15200000 7500000 2 16750000 0 415000 1100000 181500001285000 Ker-3 3 5800000 995000 16650000 35500 30100000 1400000 4 16500000 50 9500 45200000 7750000 5 12500 12500 13600000 50 18600000 6650000Ker-4 6 92000 350 5200000 8050 21400000 8250000 Row CON-IE CON-AEOnset-IE Onset-AE 1 467000000 1650000 15000 1635000 2 221500000 23500000107000 130000 PMX-Ker-3 3 202000000 5400000 132500 133000 4 11500000030500 75000 118000 5 253000000 69000000 59000 61000 PMX-Ker-4 6 15000000176000000 55500 2500 Data Display Log₁₀ CFU/ml PMX-AE P + F-IE P + F-AEFARN-IE FARN-AE Row PMX-IE Log Log Log Log Log Log 1 0.00000 0.000007.07737 2.40654 7.18184 6.87506 2 7.22401 0.00000 5.61805 6.041397.25888 6.10890 K-3 3 6.76343 5.99782 7.22141 4.55023 7.47857 6.14613 46.21748 0.00000 1.69897 3.97772 7.65514 6.88930 5 4.09691 4.096917.13354 1.69897 7.26951 6.82282 K-4 6 4.96379 2.54407 6.71600 3.905807.33041 6.91645 Row CON-IE Log CON-AE Log Onset-IE Log Onset-AE Log 18.66932 6.21748 4.17609 6.21352 2 8.34537 7.37107 5.02938 5.11394PMX-Ker-3 3 8.30535 6.73239 5.12222 5.12385 4 8.06070 4.48430 4.875065.07188 5 8.40312 7.83885 4.77085 4.78533 PMX-Ker-4 6 7.17609 8.245514.74429 3.39794 Descriptive Statistics Log₁₀ CFU/ml Total SE VariableCount Mean Mean StDev Minimum Median Maximum PMX-IE Log 6 4.88 1.08 2.660.00 5.59 7.22 PMX-AE Log 6 2.11 1.04 2.55 0.00 1.27 6.00 P + F-IE Log 65.911 0.876 2.147 1.699 6.897 7.221 P + F-AE Log 6 3.763 0.632 1.5481.699 3.942 6.041 FARN-IE Log 6 7.3624 0.0712 0.1744 7.1818 7.30007.6551 FARN-AE Log 6 6.626 0.158 0.388 6.109 6.849 6.916 CON-IE Log 68.160 0.212 0.520 7.176 8.325 8.669 CON-AE Log 6 6.815 0.554 1.356 4.4847.052 8.246 Onset-IE Log 6 4.786 0.136 0.333 4.176 4.823 5.122 Onset-AELog 6 4.951 0.370 0.906 3.398 5.093 6.214

Microbiological Results—Intact Epithelium

Kruskal-Wallis ANOVA with Duncan Multiple Comparisons Test - Log₁₀CFU/ml Row # Group/Level Mean Rank C.I. Overlaps 1 Onset-IE L 6.8333 2,3, 2 PMX-IE Log 9.6667 1, 3, 3 P + F-IE Log 12.6667 1, 2, P = 0.05 4FARN-IE Lo 22.1667 5, 5 CON-IE Log 26.1667 4, ONSET = PMX = P + F < FARN= CON

Microbiological Results—Abraded Epithelium

Kruskal-Wallis ANOVA with Duncan Multiple Comparisons Test - Log₁₀CFU/ml Row # Group/Level Mean Rank C.I. Overlaps 1 PMX-AE Log 6.5000 2,2 P + F-AE Log 9.3333 1, 3 Onset-AE L 14.3333 P = 0.05 4 FARN-AE Lo23.5000 5, 5 CON-AE Log 23.8333 4, PMX = P + F < ONSET < FARN = CON

Microbiological Results—0.25% Oligomer 4 w/o FARN vs. w/ FARN—IntactEpithelium

Mann-Whitney Test and CI: PMX-IE Log, P + F-IE Log N Median PMX-IE Log 65.591 P + F-IE Log 6 6.897 Point estimate for ETA1-ETA2 is −0.757 95.5Percent CI for ETA1-ETA2 is (−3.124, 1.607) W = 34.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.4712 NS

Microbiological Results—0.25% Oligomer 4 w/o FARN vs. w/ FARN—AbradedEpithelium

Mann-Whitney Test and CI: PMX-AE Log, P + F-AE Log N Median PMX-AE Log 61.272 P + F-AE Log 6 3.942 Point estimate for ETA1-ETA2 is −1.822 95.5Percent CI for ETA1-ETA2 is (−4.549, 1.690) W = 32.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.2980 The test is significant at0.2946 NS (adjusted for ties)Microbiological Results—Intact vs. Abraded Epithelium

Mann-Whitney Test and CI: PMX-IE Log, PMX-AE Log N Median PMX-IE Log 65.591 PMX-AE Log 6 1.272 Point estimate for ETA1-ETA2 is 3.400 95.5Percent CI for ETA1-ETA2 is (0.001, 6.764) W = 50.0 Test of ETA1 = ETA2vs ETA1 not = ETA2 is significant at 0.0927 The test is significant at0.0864 NS (adjusted for ties) Mann-Whitney Test and CI: P + F-IE Log,P + F-AE Log N Median P + F-IE Log 6 6.897 P + F-AE Log 6 3.942 Pointestimate for ETA1-ETA2 is 2.705 95.5 Percent CI for ETA1-ETA2 is(−0.423, 4.727) W = 50.5 Test of ETA1 = ETA2 vs ETA1 not = ETA2 issignificant at 0.0782 The test is significant at 0.0776 NS (adjusted forties) Mann-Whitney Test and CI: FARN-IE Log, FARN-AE Log N MedianFARN-IE Log 6 7.3000 FARN-AE Log 6 6.8489 FARN-AE < FARN-IE Pointestimate for ETA1-ETA2 is 0.5964 95.5 Percent CI for ETA1-ETA2 is(0.3588, 1.1843) W = 57.0 Test of ETA1 = ETA2 vs ETA1 not = ETA2 issignificant at 0.0051 Mann-Whitney Test and CI: CON-IE Log, CON-AE Log NMedian CON-IE Log 6 8.325 CON-AE Log 6 7.052 CON-AE < CON-IE Pointestimate for ETA1-ETA2 is 1.003 95.5 Percent CI for ETA1-ETA2 is (0.100,2.691) W = 53.0 Test of ETA1 = ETA2 vs ETA1 not = ETA2 is significant at0.0306 Mann-Whitney Test and CI: Onset-IE Log, Onset-AE Log N MedianOnset-IE Log 6 4.823 Onset-AE Log 6 5.093 Point estimate for ETA1-ETA2is −0.218 95.5 Percent CI for ETA1-ETA2 is (−1.091, 0.778) W = 32.0 Testof ETA1 = ETA2 vs ETA1 not = ETA2 is significant at 0.2980 NS

Summary of Statistical Comparisons for Microbiological Data<=Significantly Fewer Colony Counts Effect of Abraded Epithelium onEffectiveness of Each Test Solution or Onset Control

PMX Abraded = Intact P + F Abraded = Intact FARN Abraded < Intact SalineControl Abraded < Intact Onset of Therapy Control Abraded = IntactEffect of Test Solutions on Corneas with Intact Epithelium

ONSET=PMX═P+F<FARN═CON

Effect of Test Solutions on Corneas with Abraded Epithelium

PMX═P+F<ONSET<FARN═CON

Effect of Farnesol on 0.25% Oligomer 4 on Corneas with Intact Epithelium

PMX═P+F

Effect of Farnesol on 0.25% Oligomer 4 on Corneas with AbradedEpithelium

PMX═P+F Summary of Results

0.25% Oligomer 4 (PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F)were effective in reducing fluoroquinolone-resistant,methicillin-resistant Staphylococcus aureus colony counts compared withthe Saline Control in the NZW rabbit keratitis model when the cornealepithelium was intact or removed from the corneas. 0.25% Oligomer 4(PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F) were effective inreducing fluoroquinolone-resistant, methicillin-resistant Staphylococcusaureus colony counts compared with the Onset of Therapy Control in theNZW rabbit keratitis model when the corneal epithelium was removed butnot when the epithelium was intact. There was no difference influoroquinolone-resistant, methicillin-resistant Staphylococcus aureuscolony counts in the NZW rabbit keratitis model between 0.25% Oligomer 4(PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F) with intact orabraded corneal epithelium. 200 mM Farnesol alone was not effective inreducing colony counts fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus colony counts compared with the Saline Control inthe NZW rabbit keratitis model. Eyes treated with 200 mM Farnesol aloneand Saline demonstrated significantly fewer colony counts in eyes withthe corneal epithelium removed compared to those with intact epithelium.0.25% Oligomer 4 (PMX) and 0.25% Oligomer 4 with 200 mM Farnesol (P+F)and 200 mM Farnesol alone did not induce statistically greater toxicity(as manifested by higher Total Ocular Scores) compared with the Salinetreated eyes in eyes with intact or abraded corneal epithelia.

The biomimetic Oligomer 4 was effective in significantly reducing colonycounts in a fluoroquinolone-resistant, methicillin-resistantStaphylococcus aureus NZW rabbit keratitis model. Oligomer 4formulations were effective when the corneal epithelium was removedsuggesting that epithelium appears to be barrier for penetration ofOligomer 4 to the site of infection in the corneal stroma. The additionof 200 mM Farnesol did nothing to promote penetration Oligomer 4 throughintact corneal epithelium, nor did it enhance its antibacterialefficacy. In fact, a trend toward antagonism was observed. Mechanicalabrasion of the corneal epithelium alone reduced the bacterial colonycounts in the control eyes. Therefore, the lower colony counts observedin the Oligomer 4-treated abraded eyes does not necessarily indicategreater drug efficacy. No significant ocular toxicity was observed forany formulation in this rabbit keratitis model.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All documents, e.g., scientific publications,patents, patent applications, and patent publications recited herein arehereby incorporated by reference in their entirety to the same extent asif each individual document was specifically and individually indicatedto be incorporated by reference in its entirety. Where the documentcited only provides the first page of the document, the entire documentis intended, including the remaining pages of the document. Variousmodifications of the invention, in addition to those described herein,will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

1-15. (canceled)
 16. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 17. A compositioncomprising the compound of claim 16, or a pharmaceutically acceptablesalt thereof.
 18. The composition of claim 17 which is in the form of aliquid or solid.
 19. The composition of claim 17 which is in the form ofa solution, a suspension, an emulsion, a gel, or an ointment.
 20. Thecomposition of claim 17 further comprising a preservative, a stabilizer,an antioxidant, a chelating agent, or a surfactant.
 21. The compositionof claim 17 further comprising an additional medicament.
 22. Thecomposition of claim 21 wherein the additional medicament is chosen froman antibiotic, an anti-inflammatory agent, an anesthetic agent, ananti-allergic agent, an acetylcholine blocking agent, an adrenergicagonist, a beta-adrenergic blocking agent, an anti-glaucoma agent, andan anti-hypertensive agent.
 23. The composition of claim 22 wherein theantibiotic is chosen from an aminoglycoside, a cephalosporin, adiaminopyridine, a fluoroquinolone, a sulfonamide, and a tetracycline.24. The composition of claim 22 wherein the antibiotic is chosen fromamikacin, azithromycin, cefixime, cefoperazone, cefotaxime, ceftazidime,ceftizoxime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin,colistin, domeclocycline, doxycycline, erythromycin, gentamicin,mafenide, methacycline, minocycline, neomycin, norfloxacin, ofloxacin,oxytetracycline, polymyxin B, pyrimethamine, silver sulfadiazine,sulfacetamide, sulfisoxazole, tetracycline, tobramycin, andtrimethoprim.
 25. The composition of claim 22 wherein theanti-inflammatory agent is a steroidal agent.
 26. The composition ofclaim 25 wherein the steroidal agent is chosen from dexamethasone,rimexolone, prednisolone, fluorometholone, and hydrocortisone.
 27. Thecomposition of claim 22 wherein the anti-inflammatory agent is anon-steroidal agent.
 28. The composition of claim 27 wherein thenon-steroidal agent is chosen from a cyclooxygenase type I or type IIinhibitor, a PAF antagonist, a PDE IV inhibitor, and an inhibitor ofcytokine production.
 29. The composition of claim 28 wherein thecyclooxygenase type I or type II inhibitor is chosen from diclofenac,flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin,naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam,sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen,benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin,oxyphenbutazone, tenoxicam, carprofen, vioxx, celecoxib, and etodolac.30. The composition of claim 28 wherein the PAF antagonist is chosenfrom apafant, bepafant, minopafant, nupafant, and modipafant.
 31. Thecomposition of claim 28 wherein the PDE IV inhibitor is chosen fromariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline,and roflumilast.
 32. The composition of claim 22 wherein theanti-allergic agent is pemirolast or olopatadine.
 33. The composition ofclaim 22 wherein the anti-allergic agent is a corticosteroid.
 34. Thecomposition of claim 33 wherein the corticosteroid is chosen fromprednisolone, fluorometholone, loteprenol, and dexamethasone.
 35. Amethod of treating a bacterial infection in a mammal comprisingadministering to the mammal in need thereof an effective amount of thecompound of claim 16, or a pharmaceutically acceptable salt thereof, ora composition comprising the compound of claim 16, or a pharmaceuticallyacceptable salt thereof.